Targeted photodynamic therapy: enhancing efficacy through specific organelle engagement

Abstract

Photodynamic therapy (PDT) induces cancer cell death by utilizing photosensitizers to generate reactive oxygen species (ROS) upon light irradiation, which in turn trigger oxidative stress. However, the therapeutic efficacy of PDT is constrained by the short lifetimes and limited diffusion range of ROS, resulting in suboptimal outcomes and off-target effects. Specific organelle targeting, facilitated by rationally engineered photosensitizers and nanoplatforms with precise drug delivery capabilities that activate organelle-mediated cell death pathways, can maximize localized oxidative damage, enhance therapeutic efficacy, and minimize systemic toxicity. This review synthesizes advancements in organelle-targeted PDT, focusing on critical subcellular compartments (e.g., mitochondria, lysosomes, nuclei, cell membranes, ribosome, endoplasmic reticulum, golgi apparatus, autophagosome). It systematically summarizes the structural characteristics, design strategies, targeting mechanisms, and therapeutic effects of these organelle-targeted systems, with particular emphasis on organelle-mediated cell death signaling pathways. Ultimately, current challenges, prospective opportunities, and future research directions in organelle targeting are delineated, providing a strategic framework to advance organelle-targeted PDT toward precision therapy.

1 Introduction

The complexity and heterogeneity of malignant tumors are major contributors to their high mortality rate, making cancer treatment a critical challenge in nanomedicine and life sciences (Bian et al., 2024; Cantallops Vilà et al., 2024). Various approaches have been developed, including surgery, chemotherapy, radiotherapy, photodynamic therapy (PDT), immunotherapy, and gene therapy (Cortés-Guiral et al., 2021; Pan Y. et al., 2022; Xie R. et al., 2023; Qian et al., 2024). Among these, PDT has gained significant attention due to its spatiotemporal precision, low cost, ease of application, and minimal toxic side effects (Li et al., 2020; Di Bartolomeo et al., 2022). Notably, unlike conventional therapies, PDT rarely causes drug resistance or severe adverse effects (Sun B. et al., 2023; Hua et al., 2024). PDT relies on three essential components: a photosensitizer, light, and oxygen (O₂) (Kolarikova et al., 2023; Wang et al., 2023). Upon absorption of light at specific wavelengths (typically matching its absorption spectrum), the photosensitizer undergoes a transition from the ground state to an excited singlet state (S₁), followed by intersystem crossing to form a longer-lived triplet state (T₁) (Fay and Limmer, 2024; Kim et al., 2024). This T₁ species then mediates the two primary mechanisms of PDT (Figure 1A). Type II PDT is defined by energy transfer from the triplet-state photosensitizer to ground-state molecular oxygen (³O₂), which is converted into highly cytotoxic singlet oxygen (¹O₂) (Shigemitsu et al., 2022; Yu L. et al., 2024). This process is strictly O₂-dependent, as ¹O₂ generation directly relies on the availability of O₂, and the short half-life of ¹O₂ limits its diffusion to a narrow region around the photosensitizer. In contrast, Type I PDT is characterized by relatively low O₂ dependence, enabling it to retain efficacy even in hypoxic tumor regions. It operates through a distinct pathway where the excited photosensitizer, typically in its T₁, undergoes electron transfer or hydrogen atom abstraction reactions with biological substrates, such as amino acids, lipids, or nucleic acids, in the tumor microenvironment. This substrate-mediated interaction leads to the generation of a suite of reactive oxygen species (ROS), including superoxide anion radicals (•O₂⁻), hydrogen peroxide (H₂O₂), and hydroxyl radicals (•OH) (Wen et al., 2022; Zhen et al., 2025). Despite these differences in ROS generation mechanisms and oxygen requirements, both Type I and Type II PDT culminate in elevated oxidative stress in the tumor microenvironment, ultimately inducing cancer cell death (Yu Y. et al., 2023; Zhang et al., 2023d).

FIGURE 1

However, we must confront an undeniable fact: despite the increasing number of studies on PDT-based anti-tumor treatments in recent years, several critical issues still need to be addressed (Sun et al., 2022). One of the most prominent challenges is the extremely short half-life (0.03–0.18 µs) and limited action range (0.01–0.02 µm) of ¹O₂ generated by photosensitizers (Moan and Berg, 1991; Niedre et al., 2002). As a result, the oxidative effects of PDT-induced ROS are largely confined to areas in close proximity to the photosensitizer (Austin et al., 2025). To overcome this limitation, investigating the mechanism of PDT-induced immunogenic cell death (ICD) has emerged as a potentially effective strategy (Zhang et al., 2022b; Zhang T. et al., 2023). Nevertheless, an even more promising approach may lie in further enhancing the targeting capability of photosensitizer-based nanoplatforms, particularly their ability to selectively target various subcellular organelles (Sun et al., 2024). Achieving precise subcellular localization enables targeted disruption at critical sites, triggering a systemic effect that can ultimately lead to different modes of cancer cell death, including apoptosis, necrosis, or pyroptosis (Tong et al., 2024; Wang B. et al., 2024).

Cells are the fundamental units of life, and their normal metabolism is essential for maintaining health (Finley, 2023; Sun et al., 2025). Disruptions in cellular metabolism can lead to various diseases (Plikus et al., 2021; Lee et al., 2024). Such metabolic processes rely heavily on the coordinated function and communication among intracellular organelles (König and McBride, 2024; Zimmermann et al., 2024). Common organelles include mitochondria, lysosomes, endoplasmic reticulum (ER), Golgi apparatus, endosomes, and centrosomes, each playing a distinct role in cellular function (Bornens, 2021; Celik et al., 2023; Ebner et al., 2023; Meyer and Kravic, 2024; Sun S. et al., 2024). The cell membrane, as a phospholipid bilayer structure, plays a critical role in maintaining the separation and homeostasis between the intracellular and extracellular environments (Zhu X. et al., 2024). It is particularly susceptible to oxidative attack by ROS, leading to the generation of abundant lipid peroxidation (LPO) products (Pope and Dixon, 2023; Zhu et al., 2023). This not only exacerbates membrane damage but also provides a mechanistic basis for the synergistic enhancement of PDT with ferroptosis (Pan W. et al., 2022; Chen et al., 2024). Mitochondria generate adenosine triphosphate (ATP) through aerobic respiration, providing energy for cellular activities (Dong et al., 2023; Granath-Panelo and Kajimura, 2024). Upon exposure to ROS, mitochondria experience disruption of membrane potential and functional impairment, leading to reduced O₂ consumption (Cho and Kim, 2024). This creates a favorable environment for O₂-dependent PDT to generate increased levels of ROS, thereby enhancing therapeutic efficacy (Cen et al., 2023). Lysosomes degrade unwanted cellular materials via hydrolytic enzymes (Settembre and Perera, 2024; Sweet et al., 2025). Following ROS-induced damage, the permeability of the lysosomal membrane is altered, leading to the release of intracellular cathepsins that induce cell death. This mechanism opens up new avenues for cancer therapy (Yu Q. et al., 2023; Chen F. et al., 2025). The ER is crucial for the synthesis and transport of proteins and lipids, while the Golgi apparatus modifies, sorts, and transports proteins for secretion or delivery to other organelles (Weigel et al., 2021; Tang and Ginsburg, 2023). ROS-induced oxidative stress in the ER and the reduction of immunosuppressive factor secretion by the Golgi apparatus caused by ROS both provide new opportunities and mechanistic insights for enhanced PDT (Liu M. et al., 2022; Zhang X. et al., 2022). Given these critical roles, maintaining the structural and functional integrity of organelles is vital for cell survival (Yao et al., 2021; Harapas et al., 2022). Conversely, disrupting organelle function-such as by damaging membranes, altering membrane potential, or releasing destructive enzymes-can impair cellular metabolism and trigger programmed cell death, making organelles promising targets for therapeutic interventions (Šlachtová et al., 2023; Soukar et al., 2025).

Several reviews have summarized strategies for targeting specific organelles through material design to treat diseases, primarily focusing on the development of targeting agents (Yang et al., 2022; Shao et al., 2023; Ying et al., 2023; Hong et al., 2024). In contrast, this review highlights the structural features required for designing photosensitizers that target different organelles (Figure 1B). We also evaluate which organelles are most effective targets in PDT, particularly in overcoming challenges such as tumor hypoxia, drug resistance, metastasis, and recurrence. By analyzing current studies on organelle-targeted PDT, we aim to deepen the understanding of PDT’s mechanisms in inhibiting tumor growth and provide insights for its future clinical application.

2 Subcellular organelle-specific targeting mechanisms for enhanced PDT

Animal cells contain a variety of structurally and functionally distinct organelles that work in concert to maintain cellular homeostasis. These organelles not only carry out essential biological processes but also serve as potential targets for therapeutic interventions, including PDT (Liu X. et al., 2022; Xu Y. et al., 2025). Targeting specific organelles with photosensitizers can enhance PDT efficacy by inducing localized damage and activating cell death pathways (Chai et al., 2022). Below is an overview of key organelles and their functional roles relevant to PDT (Table 1).

The cell membrane acts as a selective barrier, regulating nutrient uptake and waste removal. It also plays a central role in signal transduction and intercellular communication (Bijonowski et al., 2025). Damage to the cell membrane via PDT can disrupt ion balance and trigger apoptosis (Fang R. H. et al., 2023). Moreover, it is well known that the therapeutic efficacy of PDT is not only limited by the short lifetime of ROS, but is also affected by intracellular reducing agents such as glutathione (GSH). The ROS generated during PDT can directly act on the cell membrane, inducing LPO and thereby achieving efficient tumor suppression (Deng et al., 2022). ROS can directly act on the cell membrane, effectively increasing membrane permeability, disrupting membrane integrity, and leading to the rapid release of intracellular contents, thereby inducing necroptosis cancer theranostics (Niu et al., 2022) and ICD (Tang et al., 2023).

Lysosomes are crucial for maintaining normal cellular turnover, and have been implicated in various diseases, including cancer (Zhu et al., 2020). The integrity of the lysosomal membrane is essential for its physiological functions (Cao et al., 2021). However, studies have shown that the permeability of the lysosomal membrane can be influenced by ROS, thereby inducing a cathepsin-mediated lysosomal cell death pathway, which operates distinctly from apoptosis mediated by caspases (Figure 2A) (Wu et al., 2022; Liu X. et al., 2023). Consequently, employing photosensitizers to generate ROS with the aim of altering the integrity and functionality of lysosomal membranes may emerge as a promising therapeutic strategy for cancer treatment (Chen Z. et al., 2025). In recent years, growing evidence has confirmed that lysosomes play a critical role in the activation of pyroptosis (Zheng Z. et al., 2021; Luo et al., 2024). Specifically, when lysosomes are damaged, they release cathepsin B, which subsequently activates the NLRP3 inflammasome and caspase-1, ultimately leading to pyroptotic cell death mediated by GSDMD-N (Liu et al., 2024c; Sun et al., 2024). Moreover, recent studies have indicated that alterations in lysosomal membrane permeability can impair the ability of lysosomes to maintain cellular homeostasis, ultimately leading to lysosome-mediated cell death mechanisms (Li et al., 2023; Xie Z. et al., 2023).

FIGURE 2

The Mitochondria could generate ATP through oxidative phosphorylation and play a central role in apoptosis regulation (Kilbride and Prehn, 2013; Yadav et al., 2015; Kuznetsov et al., 2022; Khaliulin et al., 2025). ROS generated during PDT can effectively disrupt the mitochondrial membrane potential, leading to mitochondrial dysfunction (Yang F. et al., 2023). This helps prevent further O₂ consumption by mitochondria, thereby enhancing the efficiency of O₂-dependent PDT in producing more ROS (Figure 2B). Moreover, studies have shown that mitochondria are highly enriched with GSH, an important antioxidant molecule (Liu Y. et al., 2023). Therefore, directly targeting mitochondria may offer a more direct way to impair cellular defense mechanisms. Mitochondrial damage is one of the most effective PDT targets due to its direct involvement in programmed cell death (Yan et al., 2024).

The Nucleus can store genetic material (DNA) and controls gene expression and cell proliferation (Sabari et al., 2020; Kalukula et al., 2022). Nuclear damage induced by PDT can lead to DNA fragmentation and irreversible cell cycle arrest (Zhang et al., 2023c). Moreover, studies have shown that photoactive materials targeting the nucleus can generate ROS upon light irradiation, which directly damage nuclear DNA (Figure 2C). The resulting cytosolic DNA fragments can then work in synergy with STING agonists to activate the innate anti-tumor immune response (Wu Y. et al., 2024; Feng et al., 2025).

Photosensitive agents targeting the ER can induce significant ER stress upon light exposure, leading to the surface expression of calreticulin (CRT) (Figure 2D) (Li et al., 2019). This process stimulates the antigen-presenting capability of dendritic cells and triggers ICD, thereby suppressing cancer cell proliferation. A number of studies have demonstrated that both ER stress and ROS production play critical roles in activating intracellular signaling pathways that regulate ICD (Deng H. et al., 2020). PDT with ER-targeting specificity can further enhance the antitumor therapeutic effect.

Research indicates that the Golgi apparatus serves as a key site for the production of various immunosuppressive cytokines. The generation of these cytokines relies on the structural integrity of the Golgi, making it an effective strategy to suppress their expression by disrupting this organelle. Therefore, PDT-induced ROS can impair Golgi function and thereby prevent the release of immunosuppressive factors, which would otherwise hinder the immune response triggered by PDT (Chen Y. J. et al., 2023). This approach enhances the overall efficacy of PDT in inhibiting cancer cell proliferation. Moreover, Golgi-targeted photosensitizers can upregulate the expression of NLRP3 upon light activation, promoting the release of pro-inflammatory cytokines such as IL-1β (Hu et al., 2023). This not only strengthens innate immunity but also boosts adaptive immune responses against tumor cells. Hence, a precise phototherapy strategy targeting the Golgi apparatus offers a promising new direction for effective tumor suppression (Shi et al., 2024).

By selectively delivering photosensitizers to specific subcellular organelles, PDT can be optimized to induce site-specific damage, thereby enhancing therapeutic efficacy and addressing key challenges such as hypoxia, drug resistance, immune suppression, and tumor recurrence (Wang et al., 2021; Tian et al., 2024). A deeper understanding of the unique biological functions and characteristics of each organelle lays the groundwork for developing more effective and precisely targeted PDT strategies.

3 Mitochondrial targeting for enhanced PDT

Cancer treatment remains one of the key research areas in the field of biomedicine (Shen et al., 2024; Wu D. et al., 2024; Ye et al., 2024; Yu et al., 2024b). The continuous development of effective and safe nanodrug delivery systems is not only crucial for advancing cancer therapy but also an urgent and ongoing research priority. Indeed, mitochondria play a pivotal role in cancer cellular energetics (Ikeda et al., 2021). Often referred to as the “powerhouses” of eukaryotic cells, these organelles are responsible for producing the majority of ATP, the cell’s universal energy currency (Wang H. et al., 2024). This process occurs through oxidative phosphorylation, a series of reactions that take place in the inner mitochondrial membrane (Vercellino and Sazanov, 2022; Decker and Funai, 2024). Developing mitochondria-targeted nanomedicine systems can enhance the therapeutic effects of PDT by leveraging the cascade of mechanisms triggered by mitochondrial dysfunction (Ding et al., 2025). A comprehensive overview of diverse mitochondria-targeted PDT strategies, spanning GSH depletion, O₂ generation, mitochondria respiration inhibition, and O₂-independent radical production, are systematically summarized in Table 2.

3.1 Targeted GSH depletion in mitochondria for enhanced PDT efficacy

Mitochondria-often referred to as the cell’s energy powerhouse-are particularly vulnerable to oxidative stress (Zhu et al., 2022). GSH is a tripeptide antioxidant present in all cells that maintains cellular redox homeostasis, with mitochondrial GSH (mGSH) playing a unique role in protecting mitochondrial DNA and respiratory chain proteins from oxidative damage (Li B. et al., 2025). Notably, mGSH is spatially and functionally distinct from cytosolic GSH: it is synthesized in the cytosol and transported into mitochondria via the glutamate-cystine antiporter (GC1), forming a relatively independent pool that accounts for ∼10–15% of total cellular GSH but is critical for mitochondrial redox defense (Lu et al., 2022; Xu T. et al., 2025). Tumor cells exhibit higher mGSH levels than normal cells, enabling them to scavenge ROS generated during PDT and resist oxidative stress (Song et al., 2024). Thus, selective depletion of mGSH rather than global GSH reduction avoids disrupting cytosolic redox balance and enhances PDT specificity (Zhang et al., 2025).

Ke et al. developed an iridium (III) complex containing thiols at both ends (Ir-SH) to construct self-assembled nanoparticles (IrS NPs) for targeted GSH depletion (Figure 3A) (Ke et al., 2022). Surface modification with Biotin, a small molecule ligand that specifically binds to overexpressed biotin receptors on tumor cells, enabling active targeting cellular uptake. Intrinsic lipophilic cationic properties of Ir-SH, which facilitates accumulation in mitochondria via electrostatic attraction to the negatively charged inner mitochondrial membrane. These nanoparticles self-assemble via disulfide bonds, which are selectively cleaved by mGSH. Upon cleavage, Ir³⁺ complexes are released, and simultaneously lowering endogenous GSH levels. Under two-photon laser irradiation, both the nanoparticles and released Ir³⁺ generate a mixture of ¹O₂ and •O₂⁻, thereby amplifying intracellular oxidative stress. The depletion of GSH combined with increased ROS production inhibits the biosynthesis of glutathione peroxidase 4 (GPX4), a key lipid repair enzyme (Zhang Y. et al., 2021). Downregulation of GPX4 is widely recognized as a hallmark of ferroptosis (Zou et al., 2024a). This study demonstrates that IrS NPs precisely trigger ferroptosis by reducing mitochondrial GSH levels and promoting ROS generation. This work offers a novel strategy for enhancing PDT through organelle-targeted approaches, potentially overcoming limitations associated with conventional apoptosis-inducing therapies and holding significant clinical potential.

FIGURE 3

Besides the direct depletion of intracellular GSH by disulfide bonds, delivering carbon monoxide (CO) has also been shown to enhance the therapeutic effect of PDT by suppressing mitochondrial biosynthesis. High doses of CO can induce apoptosis in cancer cells by inhibiting mitochondrial respiration and interfering with protein synthesis (Dong et al., 2024; Yu et al., 2024c). Porphyrin-based nMOF materials have become a major focus in phototherapy research in recent years (Zhang et al., 2024; Zou et al., 2024b; Zou et al., 2025a). However, achieving more precise treatment by targeting specific intracellular organelles may serve as a powerful driving force for further advancing the biomedical applications of nMOFs. Yang et al. designed a multi-layered targeting nanosystem (HA@MR@PCN-CORM) with hierarchical targeting strategies (Figure 3B), in which CORM-40-a transition metal carbonyl compound capable of controlled CO release-was loaded into the hollow structure of porphyrin-based PCN-224 (Yang F. et al., 2023). By surface coating with hyaluronic acid (HA), a natural polysaccharide that binds to CD44 receptors overexpressed on tumor cells, the nanosystem could realize active tumor targeting. Moreover, incorporation of a mitochondria-targeted ROS-responsive amphiphilic copolymer (MR), which contains triphenylphosphonium (TPP) groups, it could accumulate in mitochondria. The TPP groups are initially shielded by HA, preventing premature mitochondrial targeting in normal tissues. Upon HA degradation by tumor-associated hyaluronidase, TPP is exposed to mediate secondary mitochondrial targeting (Figure 3C). The core of the system is PCN-224, a porphyrin-based MOF loaded with CORM-40, a CO-releasing molecule. Under 660 nm laser irradiation, PCN-224 generates ROS, which cleaves the thioketal linker in MR, triggering controlled CO release. CO then downregulates glutamate-cysteine ligase and glutathione synthetase in 4T1 cells, inhibiting mGSH synthesis. In xenograft tumor models, HA@MR@PCN-CORM treatment led to significantly reduced levels of GPX4 and glutamate-cysteine ligase proteins, further confirming that mitochondrial CO release can sensitize cancer cells to ferroptosis through GSH suppression, thereby enhancing apoptosis and achieving effective antitumor activity.

3.2 Direct O₂ generation in mitochondria alleviates hypoxia and enhances PDT efficacy

Hypoxic tumor microenvironment remains a major obstacle limiting the efficacy of O₂-dependent PDT in suppressing cancer cell proliferation (Shen et al., 2022; Xie et al., 2024). Therefore, direct strategies to generate O₂ within tumor cells can significantly enhance PDT outcomes (Zhang et al., 2022a). Mitochondria are both major O₂ consumers via oxidative phosphorylation and key PDT targets, therefore, in situ O₂ generation within mitochondria can simultaneously replenish O₂ for ¹O₂ production and protect this organelle from hypoxic damage. The mitochondrial matrix’s unique microenvironment, such as high H₂O₂ levels and acidic pH, makes it an ideal site for catalytic O₂ generation. Numerous approaches have been developed, such as using inorganic catalysts like Mn₃O₄ and Pt nanoparticles, which react with endogenous H₂O₂ to produce O₂ (Xu et al., 2018; Zhao et al., 2023). Alternatively, catalase enzymes can be employed to directly convert H₂O₂ into O₂ (Cheng et al., 2020; Sun H. et al., 2023).

For example, Guan et al. developed mesoporous silica nanoparticles co-loaded with lipophilic cation IR780 and Mn₃O₄ nanoparticles (Figure 4A) (Yang et al., 2019). IR780, a lipophilic cationic cyanine dye, serves as the mitochondrial targeting ligand. IR780’s positive charge drives accumulation in mitochondria, while its hydrophobic structure enables insertion into the inner mitochondrial membrane. The mesoporous silica core acts as a carrier for Mn₃O₄ nanoparticles, protecting them from premature degradation and ensuring co-delivery with IR780 to mitochondria. With pH-dependent activity, Mn₃O₄ reacts with H₂O₂ to generate O₂ in mitochondrial matrix-mimicking conditions. This O₂ supply strategy enhances IR780-mediated ¹O₂ generation, while PDT-induced mitochondrial damage reduces O₂ consumption, creating a “self-amplifying” effect. Zhu et al. fabricated a hybrid nanoplatform by combining upconversion nanoparticles (UCNPs) with MOFs, and decorated the surface with platinum nanoparticles and mitochondria-targeting TPP groups (Figure 4B) (Chen Y. et al., 2023). In this system, Pt efficiently catalyzes O₂ generation from H₂O₂, alleviating tumor hypoxia and boosting PDT. Additionally, mitochondrial targeting leads to membrane depolarization and activation of apoptotic pathways, further enhancing therapeutic performance.

FIGURE 4

Beyond inorganic catalysts, enzymatic O₂ generation offers higher specificity, as catalase directly converts H₂O₂ to O₂ with high efficiency. Xu et al. catalase with rose bengal (RB) to form CAT-RB nanoparticles, where RB acts as both a photosensitizer and a mitochondrial targeting moiety via its high affinity for cardiolipin, a unique phospholipid enriched in the inner mitochondrial membrane (Figure 4C) (Xu X. et al., 2023). This cardiolipin-RB interaction ensures higher mitochondrial colocalization far exceeding cytosolic distribution. The covalent conjugation of catalase to RB through a PEG linker ensures that O₂ generated by catalase is locally retained in mitochondria, maximizing its efficacy for ¹O₂ production. After cellular uptake, CAT-RB specifically accumulate in mitochondria, maintaining high catalase activity to converts H₂O₂ into O₂, and increasing ¹O₂ production during PDT under 546 nm irradiation. The generated ROS further damage mitochondria and reduce ATP levels, promoting cancer cell apoptosis. These O₂-generating strategies are straightforward and effective, offering promising solutions to overcome hypoxia-associated limitations in PDT and significantly improving its anticancer potential.

3.3 Reduce mitochondrial respiration in mitochondria for enhanced PDT

Mitochondria is a crucial organelle targeted by PDT, and excessive ROS accumulation can initiate the mitochondrial apoptosis pathway, resulting in cell death (Zuo et al., 2021). Positioning fundamental elements of PDT into mitochondria has received considerable attention for improving ROS transportation, thus realizing PDT with high specificity (Li et al., 2021). Due to the high consumption of O₂ caused by mitochondrial respiration, sabotaging mitochondria and eliminating mitochondrial respiration are expected effective strategies to amplify the antitumor efficacy of PDT (Guo et al., 2021; Hu et al., 2024). Inhibiting respiration reduces O₂ consumption, increasing local O₂ availability for Type II PDT, while simultaneously sensitizing cells to ROS by disrupting mitochondrial membrane potential and reducing ATP-dependent repair mechanisms.

To enhance the accumulation of O₂ and photosensitizers within mitochondria precisely, hexyl 5-aminolevulinate hydrochloride (HAL) and 3-bromopyruvic acid (3BP) were simultaneously encapsulated into microparticles of X-ray irradiated tumor cells (X-MP) to prepareHAL/3BP@X-MP for potent PDT (Figure 5A) (Zuo et al., 2021). Leveraging homotypic targeting, X-MP retains tumor cell surface antigens (e.g., integrins, E-cadherin), enabling specific recognition and uptake by homologous tumor cells. The payload 3BP could serve as a small-molecule inhibitor target to hexokinase-II (HK-II), an enzyme that binds to the outer mitochondrial membrane via voltage-dependent anion channel interactions, linking glycolysis to mitochondrial respiration. 3BP covalently modifies HK-II’s active site, significantly increasing local O₂ supply by inhibiting mitochondrial respiration and glycolysis. Concurrently, HAL promotes the localized biosynthesis and effective accumulation of protoporphyrin IX (PpIX) in mitochondria via the heme biosynthesis pathway, resulting in high PpIX accumulation in mitochondria. Additionally, PpIX can produce sufficient ROS to directly destroy the mitochondria of cancer cells, leading to outstanding antitumor effects of PDT. In both in vitro/vivo experiments, the remarkable antitumor capability of HAL/3BP@X-MP could be observed without obvious side effects, providing a prospect for conquering the limitations of the PDT modality to fight hypoxic tumors.

FIGURE 5

Peptide-based respiration inhibitors could also offer high specificity. d-(KLAKLAK)₂ (dKLA), a 14-amino-acid α-helical proapoptotic peptide, has been demonstrated to damage mitochondria of eukaryotic cells, abrogate mitochondria respiration, reduce O₂ consumption (Qu et al., 2023). Accordingly, dKLA is conductive to improve the photodynamic therapeutic effect when combined with photosensitizers. Inspired by this, a charge-reversible crosslinked nanoparticle (PDC NP) based on photosensitizer chlorin e6 (Ce6) and dKLA was developed for strengthened peptide delivery efficiency and synergistic antitumor effect (Qu et al., 2023). As illustrated in Figure 5B, the proapoptotic dKLA was co-assembled with Ce6 to construct pure drug nanoparticles (DC NP) with drug loading capacity of 100%. Subsequently, a dual-aldehyde terminated PEG_2k-2CHO was utilized to crosslink the DC NP to obtain the surface charge reversal PEGylated DC NPs (PDC NP, 68.3% drug loading). Crosslinking with a dual-aldehyde PEG, theses pH-responsive NPs confer a slightly negative surface charge in blood for prolonged circulation, and undergoes charge reversal to positive in acidic tumor microenvironments, promoting cellular internalization. dKLA’s targeting mechanism relies on its cationic α-helical structure, which interacts with anionic phospholipids in the outer mitochondrial membrane and inserts into the membrane, causing depolarization. The dKLA could target and disrupt the mitochondrial membrane, and next inhibit the mitochondrial respiratory chain to reduce the consumption of local O₂. In addition, the concentration of Ce6 around mitochondria would increase in company with the targeting delivery of dKLA, thus extensively augmenting ¹O₂ production mediated by Ce6 due to increased O₂ availability. This strategy may offer a valuable approach for magnifying the drug delivery capability of peptides and optimizing mitochondrial-targeted PDT efficiency.

Apart from the well-known effect on tumor cell-killing directly, the antitumor effect induced by nitric oxide (NO) involves multiple pathways, such as nitrosation of mitochondria and DNA, as well as inhibition of cellular respiration, which is effective for overcoming drug resistance in PDT (Xu et al., 2021; Jiang et al., 2022). A mitochondria-targeted NO nanogenerator termed EArgFe@Ce6 was developed to achieve synergistic photodynamic/gas/photothermal tumor therapy (Figure 5C) (Shi et al., 2023). EGCG-Arg nanoparticles (EArg) were formed via chemical assembly of epigallocatechin gallate (EGCG) and NO donor l-Arginine (l-Arg), then EArgFe was prepared by adding ferric ions (Fe³⁺) into EArg to enable the coordination between Fe³⁺ and EGCG, and finally Ce6 was physically decorated on its surface to construct EArgFe@Ce6 (Figure 8B). Upon 660 nm light irradiation, the coordination of EGCG and Fe³⁺ endows nanogenerator with prominent photothermal capability for low-temperature PTT (Figure 8C). EGCG has verified hypoxia alleviation by inhibiting mitochondrial respiration, therefore EArgFe@Ce6 could target to and accumulate in mitochondria to suppress cell respiration, favoring the improvement of PDT. The ample ROS produced by PDT would in-turn catalyze l-Arg to synthesize considerable NO for gas therapy. The mitochondrial localized NO can suppress cell respiration and further sensitize PDT and low-temperature PTT. Together, the nanogenerator has been manifested with superior photodynamic/gas/photothermal therapeutic outcomes in in vitro and in vivo experiments, which almost achieve complete tumor ablation.

Off-target respiratory inhibition remains a challenge, as systemic delivery can affect normal tissues (e.g., heart, brain) with high O₂ demand (Xu et al., 2022; Zeng et al., 2024a). Li et al. addressed this with an “O₂ Tank” system: red blood cell membrane (RBCm)-coated perfluorocarbon (PFC) liposomes co-loaded with atovaquone (ATO, a Complex III inhibitor) and IR780 (Figure 5D) (Li X. et al., 2022). By a biomimetic stealth strategy, RBCm coating provides immune evasion and prolonged circulation, while PFC’s high O₂ solubility acts as an exogenous O₂ reservoir. Essentially, ATO, a lipophilic drug, passively accumulates in mitochondria via partitioning into lipid membranes, where it selectively inhibits Complex III of the respiratory chain, reducing tumor O₂ depletion without affecting normal tissues. IR780, as a mitochondrial-targeted photosensitizer, utilizes both endogenous (respiration-inhibited) and exogenous (PFC-delivered) O₂ to generate ¹O₂, thus boosting PDT for amplified tumor growth inhibition. This current strategy concentrates on synergistic tumor hypoxia modulation via exogenous O₂ supply and inherent O₂ metabolism, exerting the potential to augment outcomes of various therapies with hypoxia-associated resistance.

3.4 PDT with O₂-independent pathways

The therapeutic effect of photosensitizers in PDT largely depends on the ROS production efficiency and tissue penetration depth, therefore, type II PDT which relies on O₂ to produce ¹O₂ always displays insufficient effect in deep hypoxic region (Zhuang et al., 2025). In contrast, Type I PDT circumvents O₂ dependence by generating cytotoxic radicals (e.g., •O₂⁻, •OH) via electron/proton transfer reactions with endogenous donors (e.g., NADH, GSH), maintaining ROS production even when O₂ is depleted (Zheng X. et al., 2021). This O₂ independence makes Type I photosensitizers particularly valuable for treating hypoxic tumors, where they can exploit the highly reducing mitochondrial matrix (rich in redox-active molecules) to amplify radical generation (Zhuang et al., 2023).

To achieve a satisfactory PDT effect in aerobic and hypoxic scenarios simultaneously, three types of red light-emissive CDs (RCDs) derived from hypericum perforatum extract with adjustable type I/II ROS production have been developed (Li M. et al., 2025). These RCDs exhibit intrinsic mitochondrial targeting via surface amine groups, which interact electrostatically with the negatively charged inner mitochondrial membrane, achieving high mitochondrial colocalization. Their unique structural design enables dual-mode ROS generation, the RCDs exhibit tunable ROS generation with equal •O₂⁻via type I PDT and incremental ¹O₂via type II PDT, which could be adopted for deep red fluorescence imaging-guided type I/II PDT. On one hand, the unaltered core sizes of RCDs donated their same redox potentials, resulting in the production of equal •O₂⁻ (Figure 6A) (Zhang et al., 2023d). On the other hand, the enhancement of ¹O₂ production was demonstrated to be ascribed to their surface states, thus reducing the energy gaps between S₁ to T₁. With inherent mitochondria targeting ability, RCDs could precision attack towards tumors. In vitro and in vivo studies demonstrated RCDs with tunable type I/II ROS production capability, realizing a remarkable anticancer eradication even under harsh hypoxic tumor microenvironment. This work offers considerable prospects for developing versatile CDs as photosensitizers with adjustable ROS production to overcome the limitation of current single-type PDT, exhibiting substantial potential in antitumor applications.

FIGURE 6

Immunotherapy has been widely studied for cancer treatment in recent years (Chen and Wang, 2020; Hu et al., 2020; Song et al., 2022; Mao et al., 2023; Zhao et al., 2024). The combination of PDT with immunotherapy offers a promising new direction for the treatment of malignant cancer cells (Ji et al., 2022; Liu et al., 2025). Aside from directly inducing tumor cell death by PDT, ROS can further induce ICD effect for efficient tumor ablation (Huang et al., 2022; Wei et al., 2022). To improve the ROS-induced ICD effect, one soluble perylene monoimide derivative bearing tertiary ammonium functions at the imide and peri positions (PMIC-NC) was synthesized for augmented PDT therapy. Serving as a ROS supergenerator, the prepared PMIC-NC could induce Type-I/II ROS generation through electron/energy transfer upon 660 nm laser irradiation as well as trigger endogenous burst of Type I ROS assisted by proton transients in tumor cells. The excessive ROS could directly kill cells by PDT on the primary tumor, furthermore elicit vigorous ICD effect to awake antitumor immunity (cytokine secretion, DCs maturation, cytotoxic T lymphocytes activation) and thereby curb the proliferation of distant or metastasis tumors (Figure 6B) (Lou et al., 2023). After therapies, PMIC-NC supplied preferable antitumor effects on both primary tumors (suppression rate of 85.4%) and pulmonary metastasis (suppression rate of 58.1%) upon NIR irradiation. This work thus provides one proof-of-concept for the design of ROS generators which incorporates NIR light-activated Type-I/II PDT, hypoxia-triggered Type-I ROS burst and ICD effect, to realize immunogenic photochemotherapy towards hypoxic tumors.

Synergizing PDT with PTT leverages photon energy for both ROS generation and hyperthermia, with mitochondria as a critical co-target due to their sensitivity to thermal damage (Cui et al., 2023). Given that the combinational therapy of PDT and PTT may maximize treatment outcomes, Fang et al. have synthesized three mitochondria-targeting phototheranostic agents for multimodal imaging-guided PDT/PTT synergistic therapy (Figure 6C) (Fang L. et al., 2023). Attributed to the cationic pyridinium moiety, (Z)-4-(4-(2-(5-(4-(bis(4-(tert-butyl)phenyl)amino)phenyl)thiophen-2-yl)-1-cyanovinyl)phenyl)-1-ethylpyridin-1-ium bromide (STB) shows mitochondria-targeting ability via electrostatic interactions with the inner mitochondrial membrane. Employing thiophene as π bridge, STB strengthens robust donor-accepter (D-A) interactions, separates the distribution of HOMO and LUMO, enabling it with prominent NIR fluorescence emission. Moreover, the decrease of the S₁-T₁ energy gap facilitates the intersystem crossing (ISC), allowing free intramolecular rotation and resulting in massive amounts of •O₂⁻ and •OH production by optimal type I PDT. In the meantime, an ideal molar extinction coefficient and adequate intramolecular motions are beneficial for the enhancement of photothermal conversion efficiency (up to 51.9%). Based on these, STB NPs could actively target to and accumulate in the tumor site, realize real-time in vivo NIR fluorescence imaging, and obviously inhibit tumor growth with negligible side effects. This work subtly established a practical strategy by π bridge engineering, for designing phototheranostic agents with the enhancement of PDT/PTT performance, accelerating the progress of multimodal imaging-guided phototherapy against tumors.

Despite their hypoxia resistance, Type I photosensitizers face challenges: short radical lifetimes and limited intratumoral accumulation (Xiong et al., 2025). To address this, an injectable hydrogel (TSH) was engineered to co-deliver TDCAc (a Type I photosensitizer) and (NH₄)₂S (a donor of H₂S), aiming at sustained ROS generation (Figure 7A) (Zhang T. et al., 2022). Upon 660 nm laser irradiation, TDCAc would rapidly gain heat due to PTT effect, promoting the dissolution of agarose hydrogel, accelerating the release of (NH₄)₂S and TDCAc in the tumor. Afterward, H₂S gas was generated by (NH₄)₂S in an acidic tumor microenvironment, diffused into tumor cells, and then repressed intracellular catalase activity. Due to reduced H₂O₂ consumption, the in-turn accumulation of H₂O₂ could induce continuous •OH generation via the Fenton reaction by utilizing the endogenous labile iron pool in cancer cells. Notably, H₂S also upregulates mitochondrial Fe²⁺ transporters (e.g., DMT1), amplifying Fenton reactions in a feedforward loop and increasing •OH levels. The uninterrupted ROS production in cancer cells and distinguished tumor ablation have been demonstrated in vitro and in vivo. In recent years, drug delivery research based on hydrogel carriers has emerged as a promising field (Xia et al., 2023; Xu L. et al., 2023; Zhang H. et al., 2023). Combining hydrogels with phototherapy may offer new insights and strategies for the treatment of malignant cancers (Chen et al., 2021).

FIGURE 7

Two-photon excited PDT (2PE-PDT) utilizes a photosensitizer with short wavelength absorption to absorb two NIR photons and subsequently trigger ROS production, which offers an enormous possibility for precise treatment against deep tumor tissues (Wu et al., 2021; Tan et al., 2025). In this context, a series of iridium (III) complexes (Ir1-4) were synthesized, and anthraquinone was inserted in Ir4 as a mitochondrion-localized carbon radical initiator and an emission quenching group (Figure 7B) (Kuang et al., 2020). Under hypoxic conditions, this anthraquinone group within Ir4 could be specifically reduced by reductase and formed anthracene diol (Ir4-red), thus turning on the two-photon excited capability of complexes. Subsequent irradiation results in mitochondrion-localized carbon radical production, excessive intracellular ROS accumulation, and damage to mitochondrial membrane potential, resulting in cell death (IC₅₀^light = 2.1 μM). Due to the hypoxia-activated and mitochondrion-targeted merits of two-photon excitation, Ir4 has demonstrated dual functions of two-photon excited imaging (lex = 730 nm) and remarkably PDT therapy in vivo against hypoxic conditions. This metal complex-based two-photon photosensitizer could generate carbon radicals in an O₂-independent way, which is promising as a candidate for clinical treatment of hypoxic tumors.

On this basis, Kuang et al. reported a novel photoactivated prodrug (2-O-IrAn) based on the iridium (III) endoperoxide complex, which effectively united the characteristics of two-photon photosensitizers and photoactivated chemotherapy prodrugs with low dark toxicity. 2-O-IrAn targets mitochondria via its lipophilic cationic structure, achieving high colocalization with mitochondria, and is activated by NIR two-photon irradiation to release ¹O₂, alkoxy radicals, and cytotoxic precursor 2-IrAn (a mitochondrial Complex I inhibitor) (Figure 7C) (Kuang et al., 2022). This photoactivation reaction can disrupt the mitochondrial membrane and ultimately cause tumor cell death efficiently under both normal O₂ (PI = 959.1) and anaerobic conditions (PI = 690.3), appreciably enhancing the therapeutic effect of hypoxic PDT and photoactivated chemotherapy. In addition, DSPE-PEG-Biotin was introduced to endow DSPE-PEG-Biotin@2-O-IrAn nanoparticles with excellent tumor targeting and prolonged blood half-life, which could realize complete tumor eradication in vivo. This synergistic strategy of NIR two-photon photoactivated chemotherapy and PDT provides a novel guideline for the treatment of hypoxic tumors.

However, mitochondria-targeted PDT is also constrained by multi-dimensional limitations: In terms of targeting specificity, membrane potential-dependent carriers exhibit reduced localization efficiency in hypoxic tumor cells due to decreased mitochondrial membrane potential, and may be affected by variations in tumor metabolic phenotypes. At the level of carriers, metal-based nanoparticles (e.g., Pt, Ir) may interfere with mitochondrial iron-sulfur cluster synthesis to trigger chronic toxicity, peptide drugs are susceptible to protease degradation, and enzymatic catalysts show poor stability in acidic tumor microenvironments. In terms of therapeutic mechanisms, mGSH depletion may trigger compensatory elevation of cytosolic GSH, short-lived radicals tend to induce Nrf2-mediated antioxidant responses, and respiratory inhibitors may carry the risk of off-target toxicity. Additionally, excess inhibition of mitochondrial respiration may activate protective autophagy, thereby weakening therapeutic effects. These challenges collectively restrict the clinical translation and efficacy optimization of mitochondria-targeted PDT.

4 Targeting lysosome for enhanced PDT

Lysosomes are organelles that contain large amounts of cathepsin to perform key cellular catabolic processes, which are essential for maintaining cell homeostasis and regulating various cellular processes (Zhang Z. et al., 2021; Gros and Muller, 2023). Different from the normal cells, lysosomes in tumor cells are more plentiful with altered morphology, which upregulated lysosomal activity in tumor tissue is related to the metabolic need of fast proliferating tumors (He et al., 2023; Jia et al., 2023). In tumor tissue, photosensitizers localized in the lysosome may cause selective damage to lysosomes and induce subsequent cathepsin release into the cytoplasm, trigger cell death, and finally postpone the progression and metastasis of tumors.

The alteration of lysosomal membrane permeabilization (LMP) can disrupt the function of lysosomes and even cause lysosome-dependent cell death (Tanaka et al., 2022). By inhibiting the leakage of photosensitizers from lysosomes, constant LMP and unrecoverable damage to cancer cells could be motived under light irradiation, thus the efficiency of PDT substantially improved. Encourage by this, Li et al. reported lysosome-targeting nanophotosensitizer (BDQ-NP) based on boron-dipyrromethene (BOD) derivatives with an amphiphilic structure (synthesized via a reaction involving BOD core modification and hydrophobic chain conjugation) for highly effective PDT (Figure 8A) (Li et al., 2023). Amphiphilic BDQ could be synthesized in four steps by BOD and subsequently self-assembled into nano-sized particles (BDQ-NP) in aqueous solution at a concentration of 0.5 mg/mL under mild stirring (200 rpm) for 2 h. Owing to the pH-dependent lysosome-targeting property (facilitated by protonation of amino groups in the acidic lysosomal environment), BDQ powerfully incorporates into the lipid bilayers of lysosomes and induces continuous LMP through ROS-mediated LPO. Under light irradiation (660 nm, 10 mW/cm²), BDQ-NP produced a substantial amount of ROS, and disrupted functions of lysosome and mitochondria via activating the cathepsin B-mediated mitochondrial damage pathway. Specifically, cathepsin B cleaves pro-apoptotic proteins to trigger outer membrane permeabilization, releasing cytochrome c and initiating caspase-dependent apoptosis. After intravenous injection, BDQ-NP achieved high accumulation in tumors as well as a fantastic PDT effect on subcutaneous colorectal CT26 tumors and orthotopic 4T1 breast carcinomas with low systemic toxicity. In addition, PDT mediated by BDQ-NP also efficiently hindered lung metastasis of 4T1 breast carcinomas by reducing MMP-9 expression (downregulated by 42%) via lysosomal damage. This work highlights the potential value of self-assembled lysosome-targeted photosensitizers for augmented PDT effect against tumor metastasis.

FIGURE 8

The characteristics of inherent chirality, nonplanarity, and structural controllability make helicenes promising candidates in the field of optoelectronics and biomedical applications (Bouz et al., 2025). Nevertheless, the poor water solubility of helicenes strictly restricts their biological applications for organelle-targeted type I and II PDT (Yang et al., 2024). To overcome these limitations, water-soluble nanoparticles named D7H-NPs comprising twisted double [7]carbohelicene (D7H) were fabricated for lysosome-targeted bioimaging and advanced PDT (Zhao et al., 2022). As shown in Figure 8B, D7H was reprecipitated with amphiphilic 1,2-distearoyl-sn-glycero-3-phosphoethanolamine N-[methoxy (polyethylene glycol)-2000] (DSPE-PEG2000) to prepare self-assembled D7H-NPs via the nanoprecipitation method (Zhao et al., 2022). The resulting D7H-NPs displayed a uniform size of 46 ± 2 nm and exhibited superior water solubility. Especially, D7H-NPs could specifically gather in the lysosomes of 4T1 tumor cells, suggesting their ability of lysosome-targeted bioimaging. Moreover, the extensive production of •O₂⁻ and ¹O₂ derived from D7H-NPs was noticed upon light excitation, thereby triggering tumor cell apoptosis. This work contributes a promising phototherapeutic agent based on helicenes concerning type I/II PDT, manifesting a facile strategy for organelle-targeted enhanced PDT therapy.

On account of light-triggered lysosomal disruption is beneficial for tumor therapy, a photo-activable theranostic nanoplatform (TPIMBS NPs) based on a synthetic multifunctional molecule (TPIMBS, chemical structure containing a cyanine dye core, organosilver moiety, and PEGylated segment) was constructed for spatiotemporally-controllable synergistic tumor therapy (Figure 8C) (Liu X. et al., 2023). With rational design, the synthetic TPIMBS photosensitizer exhibited function of aggregation-induced NIR emission and utilized organosilver as a chemotherapeutic agent. The amphiphilic block copolymers (DSPE-PEG-2000) at a mass ratio of 1:3 (TPIMBS:polymer) was introduced to assisted TPIMBS self-assemble into nanoparticles, rendering TPIMBS NPs a prolonged blood circulation half-life time of 12.5 h as well as expanded tumor accumulation via passive targeting. Through photochemical internalization, TPIMBS NPs favorably focused on the lysosomes of tumor cells and created ROS under light irradiation, leading to lysosomal disruption and release of Ag⁺ and cathepsin B from TPIMBS NPs. Cathepsin B contributes to both mitochondrial damage and inflammasome activation via the NLRP3 inflammasome/caspase-1/GSDMD-N pathway. Moreover, the release Ag⁺ could serve as a chemotherapeutic agent, which inhibits thioredoxin reductase and DNA polymerase to block multiple enzymatic pathways and result in cell apoptosis, significantly boosting the systemic antitumor efficacy by synergism with PDT (tumor inhibition rate = 91% vs. 65% for monotherapy). Notably, TPIMBS NPs with excellent stability can persevere accumulation at the tumor site for up to 36 h for prolonged bioimaging, and possess the desirable capability for tumor elimination in in vivo experiments. This nanoplatform exploits the combination of lysosomal-targeted ROS production with the photoactivable release of chemotherapeutic Ag⁺, to realize a spatiotemporally-controllable antitumor effect.

Accumulating evidence demonstrates that regular lysosomal function plays a critical role in autophagic degradation and the activation of pyroptosis (Liu Y. et al., 2024; Zhu et al., 2025). Inspired by the function of lysosome closely related to pyroptosis and autophagy, Sun et al. rationally synthesized a boron-dipyrromethene dimer (BDPd) comprising two lysosomal-targeted morpholine groups as NIR photosensitizer to augment PDT/PTT (Figure 8D) (Sun et al., 2024). To facilitate internalization into cancer cells, the synthesized BDPd was further self-assembled together with amphiphilic triblock copolymer (Pluronic F127) to prepare nanosized micelles (named BDPd NPs). BDPd NPs exhibited good biocompatibility, high ROS production yield, and excellent photothermal abilities. The perfect lysosomal-targeting capability endows BDPd NPs accumulating in lysosomes and stimulates vigorous lysosomal damage by boosted ROS under NIR laser irradiation, thus increasing the killing efficiency of 4T1 cancer cells. Mechanistically, BDPd NPs could efficiently damage the lysosomal and mitochondrial of cancer cells, activate ICD marker exposure, and trigger pyroptosis through simultaneously stimulating caspase-3/GSDME and NLRP3/GSDMD pathway, subsequently promoting DCs maturation. More importantly, the destruction of lysosomal functions in-turn blocks self-protective autophagic degradation, thus losing cytoprotection towards cancer cells. Either intratumoral or intravenous injection, BDPd NPs substantially suppressed tumor growth upon NIR light activation, provoked robust antitumor immune responses, and prevented tumor recurrence in breast tumor-bearing mouse models. Collectively, this work highlights the close relationship between subcellular organelles and PTT/PDT with advanced nanotechnology, to amplify the therapeutic outcomes in the future.

5 Targeting nucleus for enhanced PDT

Metabolism imbalance advances the tumor aggressiveness and resistance towards therapies, therefore cell nucleus regulating cellular metabolism and heredity becomes a brightening subcellular therapeutic location (Pham et al., 2023). Nucleus-targeted photosensitizers can apply pressure to DNA replication, facilitate apoptosis of cancer cells, as well as provoke inflammatory cells via secreting extensively proinflammatory factors and stimulate antitumor immune response (Liu et al., 2021). Targeting the DNA damage response and DNA repair capacity in cancer cells has been recognized as an important anti-cancer strategy in recent years (Chen M. et al., 2023). Accordingly, manners to target the nucleus of tumor cells are considered a perfect target for opening the complete potential of tumor phototherapy (Wang P. et al., 2024). However, nucleus-targeting drugs with high efficiency and biosafety characteristic are recently rare.

Encouraged by nucleus-targeting photosensitizers-mediated PDT can elicit innate immune response for long-term immunotherapy, the combination of aPD-L1 with photoimmunotherapy is promising for reversing the immunosuppressive microenvironment and minimizing tumor recurrence (Zhang et al., 2023c). Zhang et al. constructed a novel nanomaterial named as PZGE by employing graphene quantum dots (GQDs) to loaded PD-L1 molecular antibody (aPD-L1) and zinc phthalocyanine (ZnPc) to promote innate immune response and transpose immunosuppressive microenvironment (Figure 9A) (Zhang et al., 2023c). To investigate the relationship between nucleus entry capacity and nanoparticle size, PZGE with three different particle sizes (5 nm, 32 nm, 200 nm) were synthesized. Then, the CCK-8 assay was employed to quantify their phototoxicity (Xiong et al., 2020; Cheng et al., 2021; Hu et al., 2021). Notably, PZGE with particle size of 5 nm exhibited the best nucleus enrichment ability due to its ultrasmall size, and amplified DNA destruction by nucleus-located PDT. Antitumor immunity was activated via cGAS/STING/IFN I pathway, followed by cytotoxic T lymphocyte infiltration and PD-L1 expression reversion. Besides, PZGE upon light irradiation effective inhibited the oral squamous cell carcinoma in vivo. Immunotherapy has introduced innovative design concepts and broad application prospects for the treatment of malignant tumors (Ge et al., 2023; Huang et al., 2023). The combination of phototherapy and immunotherapy offers a promising new approach in the fight against cancer (Liang et al., 2023). This work displays a size-dependent strategy of nucleus-targeted PDT and provides new insight into nucleus-targeting photo-mediated immunotherapy for “immune cold” tumors.

FIGURE 9

The combination of PDT and STING agonists has been shown to strongly augment the efficacy of antitumor therapy, so local delivery of photosensitizers and STING agonists based on nanoplatforms is expected to maximize tumor elimination (Ding et al., 2024). A nucleus-targeted chimeric peptide nanorod referred PFPD was constructed for antitumor precision therapy, which could enhance innate immunity through PDT-mediated local DNA damage and STING activation. Utilizing intermolecular forces, a photosensitizer (protoporphyrin IX, PpIX) was coupled onto multifunctional FFVLKPKKKRKV peptide and a novel chimeric peptide (PpIX-FFVLK-PKKKPRV) produced, which was self-assembled to form nanorods and loaded with DMXAA (a STING agonist) (Figure 9B) (Wu Y. et al., 2024). PFPD has a uniform and small size distribution with good stability, rendering its intratumor accumulation, cell internalization, and nucleus-targeted delivery of payloads. When exposure to laser, large amounts of ¹O₂ produced by PFPD induces in situ DNA fragmentation in nucleus, while the released cytoplasmic DNA fragments subsequently combined with the STING agonist to stimulate innate antitumor immunity. In addition, PFPD triggered ICD effect through nucleus-localized PDT, activated natural killer cells (NKs) and T cells, thus effectively eradicating primary and metastatic tumors with ignorable side effects. This research offers valuables for precise drug delivery and combination therapy against metastatic tumors with poor prognosis.

To deliver drugs to the nucleus of tumor cells more accurately, a hierarchical targeting cascade system towards tumor cells and the nucleus has been developed for tumor eradication through self-enhancement of PDT and chemotherapy. Specifically, a nucleus-targeting nanoprodrugs named HPC-CAT/CL were prepared based on human serum albumin (HSA), Ce6, a cisplatin prodrug (Pt (IV)), catalase (CAT), and b-cyclodextrin-lysine (CL) (Yang et al., 2023c). Then, the surface functionalization of HPC-CAT/CL was performed by a targeting agent (AS1411 aptamer), and the resulting HPC-CAT/CL-AP could actively target tumors, thus achieving self-reinforcing cascade photochemotherapy. HPC-CAT/CL-AP were efficiently taken up by tumor cells and accumulated in the nucleus, and non-toxic Pt (IV) prodrug was effectively reduced to its active state Pt (II) and supplied H₂O₂ simultaneously when exposed to overexpressed GSH in tumor cells and nucleus. Noteworthy, H₂O₂ could be decomposed by CAT to produce O₂, which effectively alleviated the influence of anaerobic environment on the curative effect of PDT, and accordingly realized the synergistic photochemotherapy effect. The in vitro and in vivo experiments showed that HPC-CAT/CL-AP was highly successful to kill tumor cells, significantly repressing tumor growth and lung metastasis. This nucleus-targeted self-augmenting cascade photochemotherapy strategy has enormous potential in overcoming recurrence and metastasis of tumors.

Beyond traditional nucleus-targeting strategies (e.g., size control, peptide-mediated delivery, and oligonucleotide aptamers targeting nuclear proteins), recent advances in s in nucleus-targeted PDT have focused on specific recognition of nuclear nucleic acids, including G-quadruplexes (G4s) and general RNA/DNA, to enhance targeting precision and therapeutic efficacy (Long et al., 2024; Chen W. et al., 2025).​ G4s are stable secondary structures formed by guanine-rich nucleic acids in oncogene promoters and telomeres, making them attractive targets for selective tumor intervention (Liu et al., 2024a). Building on this foundation, an advanced donor-π-acceptor (D-π-A) acridinium-based Type I photosensitizer was developed for RNA G4s targeting (Chen W. et al., 2023). Its structure integrates triphenylamine (electron donor) and pyridinium (electron acceptor) to achieve NIR absorption and efficient electron transfer. This acridinium derivative specifically recognizes RNA G4s through hydrogen bonding, with negligible affinity for double-stranded DNA or single-stranded RNA. Upon light irradiation, it predominantly generates •O₂⁻, instead of ¹O₂, overcoming hypoxia-induced PDT resistance and enhancing ICD in tumors.

Additionally, direct targeting of nuclear RNA/DNA via sequence complementarity or intercalation has also advanced PDT precision. A nucleus-targeted activatable photosensitive probe (CMT-I) was designed and synthesized for DNA targeting (Liao et al., 2025). Molecular docking analyses indicate that CMT-I binds to DNA selectively, relying on hydrogen bonds and π-π conjugation for interaction. In vitro spectral tests show that ct-DNA specifically activates CMT-I, leading to a notable fluorescence enhancement upon binding. When irradiated with light, CMT-I proves effective at generating ¹O₂ RNA sequencing studies reveal that the PDT induced by CMT-I activates tumor cell immunity, initiating an adaptive immune response. In vivo therapeutic trials further confirm that CMT-I boosts antitumor immunity, a key factor in successfully eliminating immunologically cold tumors, and underscores the value of nucleus-targeted PDT for precise cancer treatment. Together, these G4-and nucleic acid-targeted approaches represent a paradigm shift from broad nuclear localization to molecularly precise damage, with successive advancements significantly improving PDT efficacy and reducing systemic toxicity.​

6 Targeting cell membrane for enhanced PDT

Due to ROS possess a short half-life and a restricted effective diffusion radius, the introduction of photosensitizers to produce ROS in situ on target organelles is essential to avoid their rapid decay. Among these, the plentiful unsaturated lipids of the plasma membrane can stimulate LPO under the action of ROS produced by PDT, thus damaging the cell integrity (Fan et al., 2021). Therefore, photosensitizer-based cell membrane-targeted delivery systems can improve membrane permeability, cause LPO, disrupt membrane integrity, and ultimately result in cell membrane disruption and release of cell payloads (Wang M. et al., 2022). In recent years, membrane-targeted photosensitizer systems have been established, which could deliver photosensitizers to therapeutic target organelles to enhance the efficiency of PDT (Yang et al., 2023b).

To amerliorate phototherapy-mediated tumor metastasis suppression, self-delivery chimeric peptide (C₁₆-CypateRRKK-PEG₈-COOH, CCP) was designed for cell membrane-targeted low-temperature PTT and PDT combination therapy. As depicted in Figure 10A, CCP was constructed from palmtic acid-modified NIR dye (Cypate, hydrophobic) and chimeric peptide Arg-Arg-Lys-Lys-PEG₈ (RRKK-PEG₈-COOH, hydrophilic), whose amphiphilicity gives it the ability to self-assemble into nanoparticles (CCP NPs) (Chen et al., 2022). Among them, Cypate is a photosensitive agent for clinical use with dual effects of PDT and PTT (Zou et al., 2025b), positively charged RRKK fragment and alkyl chain of palmitic acid enable CPPs to target and insert into the cell membrane, and PEG chain endows prolong the blood circulation time of CCP NPs. CCP NPs exhibited strong tumor targeting and accumulation capability, which could effectively kill tumor cells. Under NIR laser irradiation, CCP NPs can produce numerous ROS and mild heat of less than 45 °C locally in the cell membrane, destroy the cancer cell membrane, effectively induce ICD, and activate antitumor immune response, thereby eliminating residual tumor cells. Under single administration and NIR light irradiation, CCP NPs significantly inhibited tumor growth and lung metastasis, thus extending the survival time of mice. This unique cell membrane-targeted phototherapy strategy helps to achieve tumor clearance and inhibit metastasis in a safe and effective manner.

FIGURE 10

As a form of programmed cell death caused by inflammasome, pyroptosis is an important means to overcome drug resistance towards apoptosis and fight against immunosuppressive tumor microenvironment, and ultimately inhibit tumor growth (Loveless et al., 2021; Zhu Y. et al., 2024). However, the current pyroptosis-induced drugs have some limitations, such as high toxicity, poor stability, and low intracellular accumulation. In view of this, a cell membrane-targeting photosensitizer dimer (D1) with aggregation-induced emission properties was constructed for synergistic pyroptosis-mediated photodynamic and photothermal immunotherapy. In detail, a π-conjugated chromophore with strong intramolecular charge transfer ability was formed by thiophene, triphenylamine, and pyridinium groups, and then linked two chromophores with one flexible octyl group to construct the dimeric photosensitizer D1 (Figure 10B) (Tang et al., 2023). This photosensitive dimer D1 could specially accumulate on the cell membrane, and generate ROS by type I PDT as well as heat energy by PTT under light irradiation, enabling a reinforced pyroptosis effect. Additionally, the pyroptosis triggered by synergistic phototherapy effectively triggered the discharge of inflammatory cytokines and intracellular contents, promoted tumor-specific antigen induction and DCs maturation, and stimulated T cell proliferation, thus activating systemic antitumor immunity. In mechanism, D1 exhibits improved permeability and retention effect in the tumor cell membrane, high ROS-generated efficiency, and strong photothermal effect, which accelerates pyroptosis-mediated synergistic PDT/PTT/immunotherapy in mouse models. After 7 days of treatment with laser irradiation, D1 was found to completely eliminate the primary tumors and effectively inhibit the distant tumors. This work provides a promising strategy for a satisfactory antitumor effect and rouses systemic immune response against tumor metastasis.

By self-assembly of chemotherapeutic agent sorafenib and plasma membrane-targeted amphiphilic chimeric peptide (Pal-K(PpIX)-R₄), Deng et al. have successfully prepared a nanoscale photooxidant named as SCPP (Figure 10C) (Deng et al., 2022). Among them, the palmitic part and positively charged peptide of Pal-K(PpIX)-R₄ (hydrophobic) given the SCPP plasma membrane-targeting capability. SCPP displayed excellent stability and ideal size distribution, which could enhance localized LPO production by in situ PDT with laser. In addition, intracellular accumulation of the chemotherapy drug (sorafenib) can downregulate the levels of GSH and glutathione peroxidase 4 (GPX4) by blocking the expression of cystine/glutamate antiporter (SLC7A11), thereby amplifying the PDT effect and disrupting the antioxidant defense system. Therefore, SCPP could trigger LPO through plasma membrane-targeting PDT, and activate ferroptosis of tumor cells through sorafenib-mediated chemotherapy, finally exhibiting superior tumor inhibition ability in vivo. This work may afford scientific direction for plasma membrane-targeted synergistic treatment of tumors when exposure to disadvantage conditions.

7 Targeting ribosome for enhanced PDT

Ribosomes are highly complex cellular machines, primarily composed of ribosomal RNA (rRNA) and dozens of different ribosomal proteins (R-proteins); the exact number varies slightly between species (Cheng et al., 2024). These ribosomal proteins and rRNA are arranged into two subunits of different sizes, commonly referred to as the small and large subunits of the ribosome (Elhamamsy et al., 2022). These subunits work together to convert mRNA into polypeptide chains during protein synthesis (Jiao et al., 2023). It has been reported that cancer stem cells (CSCs) have a higher abundance of ribosomes than those found in normal cells, which is one of the important markers of CSCs (Xue et al., 2024). The proportion of ribosomes in the body determines the total proteome and the rate of cell division, thus influencing the cell cycle and its fate. Due to the negative charges of ribosomes, positively charged materials interact strongly with ribosomes to achieve targeting. Qin’s group (Figure 11) first synthesized a positively charged photosensitizer (meso-Tetra (4-aminophenyl)Porphyrin, m-TAPP) and small peptides (N-fluorenylmethoxycarbonyl-leucine-leucine-leucine-OMe, Fmoc-L3-OMe) that co-assemble into nanoparticles based on π-π interactions (Wang J. et al., 2022). The pH of tumor cells is 6.5 lower than that of normal cells, which allows the positively charged co-assembly to interact strongly with ribosomes for effective targeting. The co-assembly exhibits strong ROS production under light irradiation, significantly reducing tumor stem cells and deactivating ribosomes, and inhibiting tumor cell growth both in vitro and in vivo.

FIGURE 11

8 Targeting endoplasmic reticulum for enhanced PDT

The ER is a multifunctional organelle responsible for maintaining cell homeostasis, protein synthesis, folding, and secretion. The production of ROS by PDT could disrupt the protein-folding capacity of this organelle and trigger ER stress, which leads to tumor cell death (Diao et al., 2025). Therefore, targeting the ER is critical to evoke ER stress.

8.1 Paraxin

Pardaxin, served as ER-targeting peptides, combined with a photosensitizer, were delivered to the ER to induce ICD via ER stress. You et al. designed pardaxin-modified and indocyanine green (ICG) conjugated multifunctional nanoparticles (Figure 12A), as well as O₂-carrying hemoglobin (Hb) liposomes (FAL-Hb lipo) to reverse hypoxia (Li et al., 2019). In the hypoxic tumor environment, this system showed a special affinity for the ER and produced ¹O₂ species under light irradiation. The ER-localized ¹O₂ species triggered strong ER stress and calreticulin (CRT) exposure on the cell surface as an “eat me” signal. CRT, a biomarker of ICD, promotes the maturation of dendritic cells (DCs) and further induces an immunological response, including CD8⁺ T cell proliferation and cytotoxic cytokine secretion. Finally, the ER-targeting nanosystem achieves enhanced antitumor effects. In 2022, this group reported another ER-targeting nanoparticle (Pardaxin-ICG-Liposome) (Figure 12B) fabricated through microfluidic techniques (Liu X. et al., 2022). Under near-infrared (NIR) irradiation, Pardaxin-ICG-Liposome could produce an ICD effect and activate the immune system by ER-targeting PDT.

FIGURE 12

8.2 p-Toluenesulfonamide

p-Toluenesulfonamide has been reported to target ER by binding to the sulfonamide receptor (Zhu et al., 2021). Song et al. synthesized reduction-responsive Ds-sP nanoparticles encapsulating an ER-targeting photosensitizer (Figure 12C), TCPP-TER (Deng H. et al., 2020). The Ds-sP/TCPP-TER nanoparticles could accumulate in the ER and generate ROS to trigger ER stress under 670 nm laser irradiation, resulting in an enhanced ICD effect. The amplified ICD then induced dendritic cell (DC) activation, leading to an augmented immune response, including the infiltration of CD8⁺ T cells and enhanced secretion of cytokines. Therefore, the ER-targeting Ds-sP/TCPP-TER exhibited a better antitumor effect compared to Ds-sP/TCPP. Additionally, Yoon et al. designed p-Toluenesulfonamide-modified hemicyanine dyes (ER-ZS) (Figure 12D), which are type I photosensitizers, capable of producing •O₂⁻ and •OH radicals under light irradiation (Zeng et al., 2024b). The numerous ROS generated in the ER could effectively damage it, activating the pyroptosis cascade pathway, and subsequently causing DNA breakage and effectively inhibiting tumor growth.

8.3 Others

Wong and colleagues developed a rhodamine-decorated iridium (III) complex by modifying the cyclometallating ligand to enhance the production of ROS and to achieve specific localization in the ER (Figure 13A) (Zhou et al., 2020). The replacement of the bipyridine (ppy) chelating ligand with 2,3-diphenylquinoxaline (dpqx) resulted in the complex Ir-Rho-G2, which demonstrated a higher ¹O₂ generation quantum yield and a lower luminescence quantum yield compared to Ir-Rho, thereby enhancing its ROS generation capability. Additionally, the dpqx ligand in Ir-Rho-G2 conferred a predominant and specific intracellular localization to the ER. Consequently, the cytotoxicity of Ir-Rho-G2 was approximately three times greater than that of Ir-Rho under lamp irradiation, attributable to its ability to disrupt protein folding in the ER and to activate ER stress-induced apoptosis pathways. In vivo PDT experiments, Ir-Rho-G2 effectively targeted the tumor site and suppressed tumor growth.

FIGURE 13

Tang’s group (Figure 13B) described two Type I photosensitizers, α-TPA-PIO and β-TPA-PIO, both derived from phosphindole oxide (Zhuang et al., 2020). These photosensitizers demonstrated selective accumulation in the ER, with β-TPA-PIO exhibiting a higher tumor inhibition efficiency under light irradiation than α-TPA-PIO, owing to its enhanced ROS generation capacity. In vivo, β-TPA-PIO was shown to effectively destroy tumor cells while maintaining good biocompatibility. The ER stress elicited by the excessive production of local ROS could activate apoptosis and autophagy pathways, thereby contributing to a significant PDT effect.

Peng et al. designed three types of fluorinated thio-pentamethine dyes, with TCy5-Ph-3F exhibiting the highest ¹O₂ generation efficiency and cell killing ability compared to TCy5-Ph-2F and TCy5-Ph-CF3 (Figure 13C) (Ma et al., 2022). The half-maximal inhibitory concentration (IC₅₀) of TCy5-Ph-3F was 125 nM following LED light irradiation for 10 min, significantly lower than that of TCy5-Ph-2F (IC₅₀ ∼0.5 μM) and TCy5-Ph-CF3 (IC₅₀ > 1 μM). TCy5-Ph-3F localized spontaneously to the ER with a Pearson correlation coefficient of 0.96. In vitro studies demonstrated that ROS production by TCy5-Ph-3F within the ER can induce enhanced ER stress and trigger the ICD cascade in cancer cells. In vivo, the efficacy of TCy5-Ph-3F in inhibiting primary and distant tumor growth under light irradiation exceeded that of the TCy5-Ph-2F group, attributable to an ER-targeting activated immune response.

9 Targeting golgi apparatus for enhanced PDT

The Golgi apparatus (GA) functions as a vital organelle in the intracellular membrane transport network, acting as a crossroads for extracellular and intracellular pathways (Xu et al., 2024). It is fundamental in the processing, sorting, and trafficking of proteins synthesized within the cell, ensuring their proper delivery to the intended destinations. The generation of ROS can adversely affect the structure and function of the GA, potentially leading to modifications in stress signaling pathways downstream (Hu et al., 2023). Such alterations may play a role in inhibiting tumor cell growth, contributing to the activation of cellular stress responses such as apoptosis or cell cycle arrest.

9.1 Chondroitin sulfate

Chondroitin sulfate, a polysaccharide abundant in the extracellular matrix and on cell surfaces, possesses a sugar chain structure consisting of glucuronic acid and N-acetylgalactosamine (GalNAc) (Li H. et al., 2022). This structure enables it to bind to the surface receptor GalNAc-T1, specifically targeting the Golgi apparatus of tumor cells. For example, Gong and colleagues designed a nanodrug based on chondroitin sulfate that encapsulates the photosensitizer chlorin e6 (Ce6), retinoic acid (RA), and a CpG oligodeoxynucleotide (Figure 14A) (Li H. et al., 2022). The production of ROS by this nanodrug can damage tumor cells, and the immunosuppressive effects of PDT are mitigated by targeting and destroying the Golgi apparatus. In a subsequent study, Dong’s group developed chondroitin sulfate-based nanoparticles (ChS-Ce6) where the photosensitizer Ce6 was covalently attached to chondroitin sulfate (Figure 14B) (Hu et al., 2023). The ChS-Ce6 nanoparticles were directed to the Golgi apparatus due to the strong interaction between chondroitin sulfate and GalNAc-T1 on the Golgi apparatus. Consequently, tumor cell growth was significantly inhibited in the ChS-Ce6 group upon laser irradiation, as chondroitin sulfate enhanced ROS production by Ce6. This increase in ROS upregulated the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), promoting the release of inflammatory contents, generating an inflammatory environment, and triggering downstream classical caspase-1-dependent pyroptosis.

FIGURE 14

9.2 Others

While other materials for targeting the Golgi apparatus do exist, Guo’s group designed aggregation-induced emission (AIE) photosensitizers, termed TPE-PyT-CPS, specifically for targeting the Golgi apparatus (Figure 14C) (Liu M. et al., 2022). These photosensitizers, modified with a CN group, are capable of forming large rod-like aggregates ranging from 200 to 400 nm in size and can target the Golgi apparatus via caveolin/raft-mediated endocytosis. The TPE-PyT-CPS, with its Golgi apparatus-targeting capability, induces oxidative stress within the Golgi apparatus and triggers mitochondrial-dependent apoptosis. This study demonstrates that photosensitizers with the ability to target the Golgi apparatus can more effectively inhibit tumor growth, providing a novel strategy for precise and efficient tumor therapy.

Qi’s group developed an aggregation-induced emission (AIE) photosensitizer, TPPI, which combines a cationic triphenylamine-based photosensitizer with the cyclooxygenase (COX-2) inhibitor Indomethacin (IMC) (Figure 15D) (Wang X. et al., 2024). COX-2 is overproduced and accumulated in the Golgi apparatus, allowing TPPI to specifically target the Golgi apparatus by recognizing COX-2 through IMC. Upon light irradiation, TPPI produces an abundance of ROS, leading to the destruction of the Golgi apparatus and cell death, thereby enhancing PDT through targeted action on the Golgi apparatus. Furthermore, Wu et al. created a Golgi apparatus-targeting Ru-SL complex consisting of Ru(II) pyridine and sphingosine lipid (Zhao et al., 2021). This complex effectively localizes within the Golgi apparatus and, upon light exposure, induces damage to the apparatus, resulting in the killing of tumor cells.

FIGURE 15

10 Targeting autophagosome for enhanced PDT

Autophagy is a highly conserved lysosomal-mediated degradation process in eukaryotes. Autophagosomes, which are double-membrane vesicles formed during autophagy, encapsulate autophagy substrates and transport them to lysosomes for degradation (Liu et al., 2024b). This process is crucial for cell survival, growth, and homeostasis. Reports indicate that PDT efficacy is enhanced in tumor cells when autophagy is suppressed by inhibitors. Zhang et al. developed an adenosine-triphosphate (ATP)-regulated ion transport nanosystem, comprising a porphyrinic porous coordination network (PCN) and squaramide (SQU) (Figure 15A) (Wan et al., 2019). The release of SQU in response to high ATP levels inhibits autophagy by disrupting cellular ion homeostasis, sensitizing PDT, and improving its therapeutic efficacy. Conversely, Jin’s group studied acid-sensitive CD-Ce6-3BP nanoparticles loaded with the respiration inhibitor 3-bromopyruvate (3BP) and the photosensitizer Ce6, facilitated by host-guest interaction (Figure 15B) (Deng Y. et al., 2020). 3BP reduces intracellular O₂ consumption, alleviating tumor hypoxia, and converting autophagy from a pro-survival to a pro-death process. This excessive activation of autophagy enhances the PDT effect.

11 Conclusion

In recent years, PDT has emerged as a minimally invasive, highly regulable, and immunogenic therapeutic strategy that holds great promise in the field of cancer treatment. Despite its growing popularity and notable achievements in preclinical studies, several critical challenges remain before PDT can be widely adopted in clinical practice-particularly in improving therapeutic efficiency, enhancing targeting specificity, and overcoming tumor microenvironmental limitations. This review systematically summarizes recent advances in subcellular organelle-targeted PDT strategies aimed at enhancing therapeutic outcomes. Particular emphasis is placed on nanoplatforms designed to target mitochondria, lysosomes, the nucleus, cell membrane, Golgi apparatus, and ribosomes, with detailed discussion of their targeting mechanisms and underlying pathways that contribute to enhanced PDT efficacy. These approaches not only improve the accumulation of photosensitizers at specific organelles but also modulate key intracellular signaling and oxidative stress responses, thereby potentiating antitumor effects.

Although numerous studies have demonstrated the therapeutic potential of PDT, several key issues still need to be addressed. First, in terms of drug delivery, many currently used photosensitizers suffer from poor water solubility and limited stability in vivo, often requiring complex delivery systems for effective administration. This increases formulation complexity and may compromise bioavailability. Secondly, most photosensitizers inherently lack targeting ability and must be conjugated-either covalently or non-covalently-to targeting ligands such as peptides, antibodies, or small molecules to achieve precise subcellular localization. Such multi-step functionalization processes further complicate preparation and may lead to batch-to-batch variability. Moreover, the hypoxic tumor microenvironment remains a major obstacle to efficient ROS generation during PDT. While various strategies-such as O₂-carrying materials, catalytic H₂O₂ decomposition, or mitochondrial respiration inhibition and regulation-have shown promising results in cellular and animal models, their safety and efficacy in humans remain to be fully validated. Additionally, most conventional photosensitizers rely on visible light excitation, which limits tissue penetration and restricts their application to superficial tumors. Therefore, developing photosensitizing systems responsive to NIR or X-ray irradiation could significantly expand the clinical applicability of PDT. Finally, the high interstitial pressure and dense extracellular matrix within solid tumors pose significant barriers to effective drug delivery. As a result, the concentration of systemically administered nanomedicines reaching the tumor site is often insufficient. To address this challenge, biomimetic delivery systems-such as cell membrane-coated nanoparticles or exosome-based carriers-along with active targeting strategies may offer promising solutions to enhance tumor accumulation and therapeutic performance.

From the clinical translation perspective, subcellular organelle-targeted PDT faces multiple bottlenecks hindering its transition from lab to clinic. Insufficient pharmacokinetic data on nano-photosensitizers impedes precise control of dosage and frequency, raising clinical risks. The lack of long-term biosafety assessments is a major concern, as some nanomaterials may accumulate in vivo, causing chronic toxicity or immune reactions that require long-term monitoring. Additionally, standardizing light irradiation doses in multi-center trials is challenging, in which variations in equipment, duration, and intensity reduce result comparability, hampering unified clinical standards.​ Notably, clinical experience with second-generation photosensitizers such as ALA in treating condyloma acuminatum, encompassing administration protocols, irradiation parameters, and efficacy assessment, provides a valuable reference for the design of subcellular PDT. The steps for promoting clinical translation involve strict screening of biocompatible, stable nanocarriers (material level), comprehensive evaluation of tumor targeting/killing (cellular level), in-depth in vivo pharmacokinetic and toxicity studies (animal level), and well-designed multi-center trials (clinical level). Collaborating with regulators to develop tailored approval standards will accelerate translation of photosensitizers to clinical use.

In terms of emerging trends, interdisciplinary integration drives PDT development. Deep integration with artificial intelligence enables accurate prediction of patient responses to PDT by building tumor models and analyzing clinical data, optimizing light parameters for personalized treatment based on tumor heterogeneity. Combining with immune checkpoint inhibitors creates synergy: PDT releases tumor-associated antigens to activate immunity, while inhibitors enhance the immune system’s ability to recognize and eliminate tumor cells, strengthening systemic anti-tumor immunity. Technically, activatable photosensitizers remain inert in normal physiology but activate to generate ROS upon sensing tumor microenvironment signals (e.g., low pH, high ATP, specific enzymes), achieving precise tumor killing. Multimodal platforms integrate imaging, PDT, and PTT, with real-time imaging monitoring tumor location, size, and treatment changes to guide therapies and improve efficacy. Additionally, PDT’s applications extend beyond tumors, encompassing effective killing of bacteria, fungi, and viruses (especially drug-resistant strains) without inducing resistance, as well as clearing abnormally aggregated proteins and reducing neuroinflammation in neurodegenerative diseases.

In conclusion, by deeply exploring subcellular targeting mechanisms and combining advanced materials science with biological insights, the performance of PDT is expected to be further optimized. Especially under the premise of overcoming the above challenges, accelerating clinical translation, and keeping up with emerging trends, subcellular organelle-targeted PDT is expected to break through the limitations of existing clinical treatments in the future, achieve breakthrough expansion of clinical indications, gradually expand from the current treatment of some cancers to more disease fields, transition to a wider range of clinical applications, and make greater contributions to the cause of human health.

References

• 1

  AustinE.WangJ. Y.OzogD. M.ZeitouniN.LimH. W.JagdeoJ. (2025). Photodynamic therapy: overview and mechanism of action. J. Am. Acad. Dermatol.10.1016/j.jaad.2025.02.037

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 2

  BianX.WangW.AbudurexitiM.ZhangX.MaW.ShiG.et al (2024). Integration analysis of single-cell multi-omics reveals prostate cancer heterogeneity. Adv. Sci.11 (18), e2305724. 10.1002/advs.202305724

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 3

  BijonowskiB. M.ParkJ.BergertM.TeubertC.Diz-MuñozA.GalicM.et al (2025). Intercellular adhesion boots collective cell migration through elevated membrane tension. Nat. Commun.16 (1), 1588. 10.1038/s41467-025-56941-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 4

  BornensM. (2021). Centrosome organization and functions. Curr. Opin. Struct. Biol.66, 199–206. 10.1016/j.sbi.2020.11.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 5

  BouzG.ŽádnýJ.StorchJ.VacekJ. (2025). Chiral helical scaffolds: unlocking their potential in biomolecular interactions and biomedical applications. Biotechnol. Adv.79, 108513. 10.1016/j.biotechadv.2024.108513

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 6

  Cantallops VilàP.RavichandraA.Agirre LizasoA.PerugorriaM. J.AffòS. (2024). Heterogeneity, crosstalk, and targeting of cancer-associated fibroblasts in cholangiocarcinoma. Hepatology79 (4), 941–958. 10.1097/hep.0000000000000206

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 7

  CaoM.LuoX.WuK.HeX. (2021). Targeting lysosomes in human disease: from basic research to clinical applications. Signal Transduct. Target. Ther.6 (1), 379. 10.1038/s41392-021-00778-y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 8

  CelikC.LeeS. Y. T.YapW. S.ThibaultG. (2023). Endoplasmic reticulum stress and lipids in health and diseases. Prog. Lipid Res.89, 101198. 10.1016/j.plipres.2022.101198

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 9

  CenY.ChenX.LiuY.YuB.YanM.YangN.et al (2023). Drug induced mitochondria dysfunction to enhance photodynamic therapy of hypoxic tumors. J. Control. Release358, 654–666. 10.1016/j.jconrel.2023.05.023

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 10

  ChaiC.ZhouT.ZhuJ.TangY.XiongJ.MinX.et al (2022). Multiple light-activated photodynamic therapy of tetraphenylethylene derivative with AIE characteristics for hepatocellular carcinoma via dual-organelles targeting. Pharmaceutics14 (2), 459. 10.3390/pharmaceutics14020459

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 11

  ChenD.WangH. (2020). The clinical and immune features of CD14 in colorectal cancer identified via large-scale analysis. Int. Immunopharmacol.88, 106966. 10.1016/j.intimp.2020.106966

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 12

  ChenG.UllahA.XuG.XuZ.WangF.LiuT.et al (2021). Topically applied liposome-in-hydrogels for systematically targeted tumor photothermal therapy. Drug Deliv.28 (1), 1923–1931. 10.1080/10717544.2021.1974607

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 13

  ChenP.-L.HuangP.-Y.ChenJ.-Y.ShiQ.-Y.ZhuY.-Y.ChenY.et al (2022). A self-delivery chimeric peptide for high efficient cell membrane-targeting low-temperature photothermal/photodynamic combinational therapy and metastasis suppression of tumor. Biomaterials286, 121593. 10.1016/j.biomaterials.2022.121593

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 14

  ChenM.ZhaoE.LiM.XuM.HaoS.GaoY.et al (2023a). Kaempferol inhibits non-homologous end joining repair via regulating Ku80 stability in glioma cancer. Phytomedicine116, 154876. 10.1016/j.phymed.2023.154876

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 15

  ChenW.ZhangY.YiH. B.WangF.ChuX.JiangJ. H. (2023b). Type I photosensitizer targeting G-quadruplex RNA elicits augmented immunity for cancer ablation. Angew. Chem. Int. Ed.62 (17), e202300162. 10.1002/anie.202300162

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 16

  ChenY.YangY.DuS.RenJ.JiangH.ZhangL.et al (2023c). Mitochondria-targeting upconversion nanoparticles@MOF for multiple-enhanced photodynamic therapy in hypoxic tumor. ACS Appl. Mater. Interfaces15 (30), 35884–35894. 10.1021/acsami.3c05447

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 17

  ChenY. J.LiG. N.LiX. J.WeiL. X.FuM. J.ChengZ. L.et al (2023d). Targeting IRG1 reverses the immunosuppressive function of tumor-associated macrophages and enhances cancer immunotherapy. Sci. Adv.9 (17), eadg0654. 10.1126/sciadv.adg0654

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 18

  ChenJ.DuanZ.DengL.LiL.LiQ.QuJ.et al (2024). Cell membrane-targeting type I/II photodynamic therapy combination with FSP1 inhibition for ferroptosis-enhanced photodynamic immunotherapy. Adv. Healthc. Mater.13 (16), e2304436. 10.1002/adhm.202304436

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 19

  ChenF.TianX. F.YangT.DaiY. J.ChenD. Y.ChenH. B.et al (2025a). Lysosomal cathepsin S escape facilitates near infrared light-triggered pyroptosis via an antibody-indocyanine green conjugate. Adv. Sci.e04851. 10.1002/advs.202504851

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 20

  ChenW.MaoX. Q.WangX. Z.LiaoY. C.YinX. Y.WuH. L.et al (2025b). Data-driven discovery of near-infrared type I photosensitizers for RNA-Targeted tumor photodynamic therapy. Chem. Sci.16, 14455–14467. 10.1039/d5sc03648h

  • CrossRef
  • Google Scholar

• 21

  ChenZ.WangY.LiZ.ChenM.LiY.LuC.et al (2025c). Improving ferroptosis-mediated immunotherapy for colorectal cancer through lysosome-targeted photodynamic therapy. Mater Today Bio31, 101552. 10.1016/j.mtbio.2025.101552

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 22

  ChengX.HeL.XuJ.FangQ.YangL.XueY.et al (2020). Oxygen-producing catalase-based prodrug nanoparticles overcoming resistance in hypoxia-mediated chemo-photodynamic therapy. Acta Biomater.112, 234–249. 10.1016/j.actbio.2020.05.035

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 23

  ChengQ.ChenJ.GuoH.LuJ.-l.ZhouJ.GuoX.-y.et al (2021). Pyrroloquinoline quinone promotes mitochondrial biogenesis in rotenone-induced Parkinson’s disease model via AMPK activation. Acta Pharmacol. Sin.42 (5), 665–678. 10.1038/s41401-020-0487-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 24

  ChengY.WangS.ZhangH.LeeJ. S.NiC.GuoJ.et al (2024). A non-canonical role for a small nucleolar RNA in ribosome biogenesis and senescence. Cell187 (17), 4770–4789.e23. 10.1016/j.cell.2024.06.019

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 25

  ChoY.KimY. K. (2024). ROS-Mediated cytoplasmic localization of CARM1 induces mitochondrial fission through DRP1 methylation. Redox Biol.73, 103212. 10.1016/j.redox.2024.103212

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 26

  Cortés-GuiralD.HübnerM.AlyamiM.BhattA.CeelenW.GlehenO.et al (2021). Primary and metastatic peritoneal surface malignancies. Nat. Rev. Dis. Prim.7 (1), 91. 10.1038/s41572-021-00326-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 27

  CuiM.TangD.WangB.ZhangH.LiangG.XiaoH. (2023). Bioorthogonal guided activation of cGAS-STING by AIE photosensitizer nanoparticles for targeted tumor therapy and imaging. Adv. Mater.35 (52), e2305668. 10.1002/adma.202305668

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 28

  DeckerS. T.FunaiK. (2024). Mitochondrial membrane lipids in the regulation of bioenergetic flux. Cell Metab.36 (9), 1963–1978. 10.1016/j.cmet.2024.07.024

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 29

  DengH.ZhouZ.YangW.LinL.-s.WangS.NiuG.et al (2020a). Endoplasmic reticulum targeting to amplify immunogenic cell death for cancer immunotherapy. Nano Lett.20 (3), 1928–1933. 10.1021/acs.nanolett.9b05210

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 30

  DengY.SongP.ChenX.HuangY.HongL.JinQ.et al (2020b). 3-Bromopyruvate-conjugated nanoplatform-induced pro-death autophagy for enhanced photodynamic therapy against hypoxic tumor. ACS Nano14 (8), 9711–9727. 10.1021/acsnano.0c01350

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 31

  DengF.-A.YanM.-Y.LiuY.-B.YuB.-X.HuangJ.-Q.WangC.et al (2022). Plasma membrane-targeted photooxidant for chemotherapy-enhanced lipid peroxidation. ACS Appl. Bio Mater.5 (9), 4523–4530. 10.1021/acsabm.2c00597

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 32

  Di BartolomeoL.AltavillaD.VaccaroM.VaccaroF.SquadritoV.SquadritoF.et al (2022). Photodynamic therapy in pediatric age: current applications and future trends. Front. Pharmacol.13, 879380. 10.3389/fphar.2022.879380

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 33

  DiaoS.HeX.WuY.YinL.HuangY.ZhouW.et al (2025). Endoplasmic reticulum-targeting activatable nanophotosensitizers for hypoxia relief and enhanced photodynamic therapy. Chem. Sci.16 (24), 10909–10917. 10.1039/d5sc00534e

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 34

  DingF.LiuJ.AiK.XuC.MaoX.LiuZ.et al (2024). Simultaneous activation of pyroptosis and cGAS-STING pathway with epigenetic/photodynamic nanotheranostic for enhanced tumor photoimmunotherapy. Adv. Mater.36 (7), e2306419. 10.1002/adma.202306419

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 35

  DingQ.RhaH.YoonC.KimY.HongS. J.KimH. J.et al (2025). Regulated cell death mechanisms in mitochondria-targeted phototherapy. J. Control. Release382, 113720. 10.1016/j.jconrel.2025.113720

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 36

  DongW. T.LongL. H.DengQ.LiuD.WangJ. L.WangF.et al (2023). Mitochondrial fission drives neuronal metabolic burden to promote stress susceptibility in male mice. Nat. Metab.5 (12), 2220–2236. 10.1038/s42255-023-00924-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 37

  DongX.ZhangZ.WangR.SunJ.DongC.SunL.et al (2024). RSS and ROS sequentially activated carbon monoxide release for boosting NIR imaging-guided on-demand photodynamic therapy. Small20 (22), e2309529. 10.1002/smll.202309529

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 38

  EbnerM.PuchkovD.López-OrtegaO.MuthukottiappanP.SuY.SchmiedC.et al (2023). Nutrient-regulated control of lysosome function by signaling lipid conversion. Cell186 (24), 5328–5346.e5326. 10.1016/j.cell.2023.09.027

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 39

  ElhamamsyA. R.MetgeB. J.AlsheikhH. A.ShevdeL. A.SamantR. S. (2022). Ribosome biogenesis: a central player in cancer metastasis and therapeutic resistance. Cancer Res.82 (13), 2344–2353. 10.1158/0008-5472.Can-21-4087

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 40

  FanG. L.DengF. A.ZhouX.LiuL. S.HuangJ. Q.ZhangD. W.et al (2021). Plasma membrane targeted photodynamic O(2) economizer for hypoxic tumor therapy. Biomaterials273, 120854. 10.1016/j.biomaterials.2021.120854

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 41

  FangL.MengQ.ZhangY.SuR.XingF.YangH.et al (2023a). π Bridge engineering-boosted dual enhancement of type-I photodynamic and photothermal performance for mitochondria-targeting multimodal phototheranostics of tumor. ACS Nano17 (21), 21553–21566. 10.1021/acsnano.3c06542

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 42

  FangR. H.GaoW.ZhangL. (2023b). Targeting drugs to tumours using cell membrane-coated nanoparticles. Nat. Rev. Clin. Oncol.20 (1), 33–48. 10.1038/s41571-022-00699-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 43

  FayT. P.LimmerD. T. (2024). Unraveling the mechanisms of triplet state formation in a heavy-atom free photosensitizer. Chem. Sci.15 (18), 6726–6737. 10.1039/d4sc01369g

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 44

  FengD.KangX.WangH.HeZ.XuH.LiY.et al (2025). Photochemical bomb: precision nuclear targeting to activate cGAS-STING pathway for enhanced bladder cancer immunotherapy. Biomaterials318, 123126. 10.1016/j.biomaterials.2025.123126

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 45

  FinleyL. W. S. (2023). What is cancer metabolism?Cell186 (8), 1670–1688. 10.1016/j.cell.2023.01.038

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 46

  GeC.YangX.XinJ.GongX.WangX.KongL. (2023). Recent advances in antitumor dendritic cell vaccines. Cancer Biotherapy Radiopharm.38 (7), 450–457. 10.1089/cbr.2023.0041

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 47

  Granath-PaneloM.KajimuraS. (2024). Mitochondrial heterogeneity and adaptations to cellular needs. Nat. Cell Biol.26 (5), 674–686. 10.1038/s41556-024-01410-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 48

  GrosF.MullerS. (2023). The role of lysosomes in metabolic and autoimmune diseases. Nat. Rev. Nephrol.19 (6), 366–383. 10.1038/s41581-023-00692-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 49

  GuoX.YangN.JiW.ZhangH.DongX.ZhouZ.et al (2021). Mito-bomb: targeting mitochondria for cancer therapy. Adv. Mater.33 (43), e2007778. 10.1002/adma.202007778

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 50

  HarapasC. R.IdiiatullinaE.Al-AzabM.Hrovat-SchaaleK.ReygaertsT.SteinerA.et al (2022). Organellar homeostasis and innate immune sensing. Nat. Rev. Immunol.22 (9), 535–549. 10.1038/s41577-022-00682-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 51

  HeL.ChenJ.DengP.HuangS.LiuP.WangC.et al (2023). Lysosomal cyst(e)ine storage potentiates tolerance to oxidative stress in cancer cells. Mol. Cell83 (19), 3502–3519.e11. 10.1016/j.molcel.2023.08.032

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 52

  HongW. L.HuangH.ZengX.DuanC. Y. (2024). Targeting mitochondrial quality control: new therapeutic strategies for major diseases. Mil. Med. Res.11 (1), 59. 10.1186/s40779-024-00556-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 53

  HuM.ZhouW.WangY.YaoD.YeT.YaoY.et al (2020). Discovery of the first potent proteolysis targeting chimera (PROTAC) degrader of indoleamine 2,3-dioxygenase 1. Acta Pharm. Sin. B10 (10), 1943–1953. 10.1016/j.apsb.2020.02.010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 54

  HuY.LiD.WeiH.ZhouS.ChenW.YanX.et al (2021). Neurite extension and orientation of spiral ganglion neurons can be directed by superparamagnetic iron oxide nanoparticles in a magnetic field. Int. J. Nanomedicine16 (null), 4515–4526. 10.2147/IJN.S313673

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 55

  HuZ. C.WangB.ZhouX. G.LiangH. F.LiangB.LuH. W.et al (2023). Golgi apparatus-targeted photodynamic therapy for enhancing tumor immunogenicity by eliciting NLRP3 protein-dependent pyroptosis. ACS Nano17 (21), 21153–21169. 10.1021/acsnano.3c05005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 56

  HuX.ZhangM.QuanC.RenS.ChenW.WangJ. (2024). ROS-responsive and triple-synergistic mitochondria-targeted polymer micelles for efficient induction of ICD in tumor therapeutics. Bioact. Mater.36, 490–507. 10.1016/j.bioactmat.2024.06.038

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 57

  HuaY.TianX.ZhangX.SongG.LiuY.ZhaoY.et al (2024). Applications and challenges of photodynamic therapy in the treatment of skin malignancies. Front. Pharmacol.15, 1476228. 10.3389/fphar.2024.1476228

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 58

  HuangC.LinB.ChenC.WangH.LinX.LiuJ.et al (2022). Synergistic reinforcing of immunogenic cell death and transforming tumor-associated macrophages via a multifunctional cascade bioreactor for optimizing cancer immunotherapy. Adv. Mater.34 (51), e2207593. 10.1002/adma.202207593

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 59

  HuangP.WangM.LuZ.ShiS.WeiX.BiC.et al (2023). Putrescine accelerates the differentiation of bone marrow derived dendritic cells via inhibiting phosphorylation of STAT3 at Tyr705. Int. Immunopharmacol.116, 109739. 10.1016/j.intimp.2023.109739

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 60

  IkedaG.SantosoM. R.TadaY.LiA. M.VaskovaE.JungJ. H.et al (2021). Mitochondria-rich extracellular vesicles from autologous stem cell-derived cardiomyocytes restore energetics of ischemic myocardium. J. Am. Coll. Cardiol.77 (8), 1073–1088. 10.1016/j.jacc.2020.12.060

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 61

  JiB.WeiM.YangB. (2022). Recent advances in nanomedicines for photodynamic therapy (PDT)-driven cancer immunotherapy. Theranostics12 (1), 434–458. 10.7150/thno.67300

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 62

  JiaP.TianT.LiZ.WangY.LinY.ZengW.et al (2023). CCDC50 promotes tumor growth through regulation of lysosome homeostasis. Eur. Mol. Biol. Organ. Rep.24 (10), e56948. 10.15252/embr.202356948

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 63

  JiangL.ChenD.JinZ.XiaC.XuQ.FanM.et al (2022). Light-triggered nitric oxide release and structure transformation of peptide for enhanced intratumoral retention and sensitized photodynamic therapy. Bioact. Mater.12, 303–313. 10.1016/j.bioactmat.2021.09.035

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 64

  JiaoL.LiuY.YuX. Y.PanX.ZhangY.TuJ.et al (2023). Ribosome biogenesis in disease: new players and therapeutic targets. Signal Transduct. Target. Ther.8 (1), 15. 10.1038/s41392-022-01285-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 65

  KalukulaY.StephensA. D.LammerdingJ.GabrieleS. (2022). Mechanics and functional consequences of nuclear deformations. Nat. Rev. Mol. Cell Biol.23 (9), 583–602. 10.1038/s41580-022-00480-z

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 66

  KeL.WeiF.XieL.KargesJ.ChenY.JiL.et al (2022). A biodegradable iridium(III) coordination polymer for enhanced two-photon photodynamic therapy using an apoptosis–ferroptosis hybrid pathway. Angew. Chem. Int. Ed.61 (28), e202205429. 10.1002/anie.202205429

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 67

  KhaliulinI.HamoudiW.AmalH. (2025). The multifaceted role of mitochondria in autism spectrum disorder. Mol. Psychiatry30 (2), 629–650. 10.1038/s41380-024-02725-z

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 68

  KilbrideS. M.PrehnJ. H. M. (2013). Central roles of apoptotic proteins in mitochondrial function. Oncogene32 (22), 2703–2711. 10.1038/onc.2012.348

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 69

  KimD.RoskoM. C.CastellanoF. N.GrayT. G.TeetsT. S. (2024). Long excited-state lifetimes in three-coordinate copper(I) complexes via triplet-triplet energy transfer to pyrene-decorated isocyanides. J. Am. Chem. Soc.146 (28), 19193–19204. 10.1021/jacs.4c04288

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 70

  KolarikovaM.HosikovaB.DilenkoH.Barton-TomankovaK.ValkovaL.BajgarR.et al (2023). Photodynamic therapy: innovative approaches for antibacterial and anticancer treatments. Med. Res. Rev.43 (4), 717–774. 10.1002/med.21935

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 71

  KönigT.McBrideH. M. (2024). Mitochondrial-derived vesicles in metabolism, disease, and aging. Cell Metab.36 (1), 21–35. 10.1016/j.cmet.2023.11.014

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 72

  KuangS.SunL.ZhangX.LiaoX.ReesT. W.ZengL.et al (2020). A mitochondrion-localized two-photon photosensitizer generating carbon radicals against hypoxic tumors. Angew. Chem. Int. Ed.59 (46), 20697–20703. 10.1002/anie.202009888

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 73

  KuangS.WeiF.KargesJ.KeL.XiongK.LiaoX.et al (2022). Photodecaging of a mitochondria-localized iridium(III) endoperoxide complex for two-photon photoactivated therapy under hypoxia. J. Am. Chem. Soc.144 (9), 4091–4101. 10.1021/jacs.1c13137

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 74

  KuznetsovA. V.MargreiterR.AusserlechnerM. J.HagenbuchnerJ. (2022). The complex interplay between mitochondria, ROS and entire cellular metabolism. Antioxidants11 (10), 1995. 10.3390/antiox11101995

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 75

  LeeL. E.DokeT.MukhiD.SusztakK. (2024). The key role of altered tubule cell lipid metabolism in kidney disease development. Kidney International106 (1), 24–34. 10.1016/j.kint.2024.02.025

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 76

  LiW.YangJ.LuoL.JiangM.QinB.YinH.et al (2019). Targeting photodynamic and photothermal therapy to the endoplasmic reticulum enhances immunogenic cancer cell death. Nat. Commun.10 (1), 3349. 10.1038/s41467-019-11269-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 77

  LiX.LovellJ. F.YoonJ.ChenX. (2020). Clinical development and potential of photothermal and photodynamic therapies for cancer. Nat. Rev. Clin. Oncol.17 (11), 657–674. 10.1038/s41571-020-0410-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 78

  LiX.ZhaoY.ZhangT.XingD. (2021). Mitochondria-specific agents for photodynamic cancer therapy: a key determinant to boost the efficacy. Adv. Healthc. Mater.10 (3), e2001240. 10.1002/adhm.202001240

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 79

  LiH.DengC.TanY.DongJ.ZhaoY.WangX.et al (2022a). Chondroitin sulfate-based prodrug nanoparticles enhance photodynamic immunotherapy via golgi apparatus targeting. Acta Biomater.146, 357–369. 10.1016/j.actbio.2022.05.014

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 80

  LiX.WangH.LiZ.LiD.LuX.AiS.et al (2022b). Oxygen tank for synergistic hypoxia relief to enhance mitochondria-targeted photodynamic therapy. Biomaterials Res.26 (1), 47. 10.1186/s40824-022-00296-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 81

  LiY.HanW.GongD.LuoT.FanY.MaoJ.et al (2023). A self-assembled nanophotosensitizer targets lysosomes and induces lysosomal membrane permeabilization to enhance photodynamic therapy. Chem. Sci.14 (19), 5106–5115. 10.1039/D3SC00455D

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 82

  LiB.MingH.QinS.NiceE. C.DongJ.DuZ.et al (2025a). Redox regulation: mechanisms, biology and therapeutic targets in diseases. Signal Transduct. Target. Ther.10 (1), 72. 10.1038/s41392-024-02095-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 83

  LiM.XiongJ.ZhangY.YuL.YueL.YoonC.et al (2025b). New guidelines and definitions for type I photodynamic therapy. Chem. Soc. Rev.54, 7025–7057. 10.1039/d1cs01079d

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 84

  LiangY.WangP.LiuZ.SunH.WangQ.SunG.et al (2023). Dual stimuli-responsive micelles for imaging-guided mitochondrion-targeted photothermal/photodynamic/chemo combination therapy-induced immunogenic cell death. Int. J. Nanomed.18, 4381–4402. 10.2147/IJN.S410047

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 85

  LiaoY.LinX.HeZ.ChenJ.TangS.WangW.et al (2025). Construction of nucleus-targeted photosensitizer and highly effective photodynamic immunotherapy for cancer. Bioorg. Chem.154, 108022. 10.1016/j.bioorg.2024.108022

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 86

  LiuJ.YinY.YangL.LuB.YangZ.WangW.et al (2021). Nucleus-targeted photosensitizer nanoparticles for photothermal and photodynamic therapy of breast carcinoma. Int. J. Nanomedicine16, 1473–1485. 10.2147/ijn.S284518

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 87

  LiuM.ChenY.GuoY.YuanH.CuiT.YaoS.et al (2022a). Golgi apparatus-targeted aggregation-induced emission luminogens for effective cancer photodynamic therapy. Nat. Commun.13 (1), 2179. 10.1038/s41467-022-29872-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 88

  LiuX.LiuY.LiX.HuangJ.GuoX.ZhangJ.et al (2022b). ER-Targeting PDT converts tumors into in situ therapeutic tumor vaccines. ACS Nano16 (6), 9240–9253. 10.1021/acsnano.2c01669

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 89

  LiuX.FanD.RenY.HuangS.DingJ.LiuM.et al (2023a). Photo-activable organosilver nanosystem facilitates synergistic cancer theranostics. ACS Appl. Mater. Interfaces15 (1), 711–722. 10.1021/acsami.2c21004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 90

  LiuY.LiuS.TomarA.YenF. S.UnluG.RopekN.et al (2023b). Autoregulatory control of mitochondrial glutathione homeostasis. Science382 (6672), 820–828. 10.1126/science.adf4154

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 91

  LiuJ.SunL.HongY.DengJ.LuoQ.ZengR.et al (2024a). Near-infrared fluorescent probe for sensitive detection and imaging of DNA G4s in living cells. Spectrochimica Acta Part A Mol. Biomol. Spectrosc.318, 124489. 10.1016/j.saa.2024.124489

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 92

  LiuJ.WuY.MengS.XuP.LiS.LiY.et al (2024b). Selective autophagy in cancer: mechanisms, therapeutic implications, and future perspectives. Mol. Cancer23 (1), 22. 10.1186/s12943-024-01934-y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 93

  LiuJ.YanY.ZhangY.PanX.XiaH.ZhouJ.et al (2024c). Lysosome-mitochondria cascade targeting nanoparticle drives robust pyroptosis for cancer immunotherapy. J. Am. Chem. Soc.146 (50), 34568–34582. 10.1021/jacs.4c12264

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 94

  LiuY.GuoY.ZengQ.HuY.HeR.MaW.et al (2024d). Prosapogenin a induces GSDME-dependent pyroptosis of anaplastic thyroid cancer through vacuolar ATPase activation-mediated lysosomal over-acidification. Cell death Dis.15 (8), 586. 10.1038/s41419-024-06985-z

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 95

  LiuX.HuangJ.ZhouH.WangS.GuoX.MaoJ.et al (2025). Inhibition of PDT-induced PGE2 surge for enhanced photo-immunotherapy. Biomaterials317, 123116. 10.1016/j.biomaterials.2025.123116

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 96

  LongS.ZhouJ.ZhengY.XiaoQ.LiY.YinZ.et al (2024). A NIR fluorescent probe with large stokes shift for sensitive detection and imaging of G4s in live cells. J. Photochem. Photobiol. A Chem.455, 115783. 10.1016/j.jphotochem.2024.115783

  • CrossRef
  • Google Scholar

• 97

  LouX.WangH.LiuY.HuangY.LiuZ.ZhangW.et al (2023). Perylene-based reactive oxygen species supergenerator for immunogenic photochemotherapy against hypoxic tumors. Angew. Chem. Int. Ed.62 (11), e202214586. 10.1002/anie.202214586

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 98

  LovelessR.BloomquistR.TengY. (2021). Pyroptosis at the forefront of anticancer immunity. Journal Exp. Clin. Cancer Res.40 (1), 264. 10.1186/s13046-021-02065-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 99

  LuJ.MaoY.FengS.LiX.GaoY.ZhaoQ.et al (2022). Biomimetic smart mesoporous carbon nanozyme as a dual-GSH depletion agent and O(2) generator for enhanced photodynamic therapy. Acta Biomater.148, 310–322. 10.1016/j.actbio.2022.06.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 100

  LuoY.GuanB.DengX.BaiP.HuangH.MiaoC.et al (2024). Methuosis inducer SGI-1027 cooperates with everolimus to promote apoptosis and pyroptosis by triggering lysosomal membrane permeability in renal cancer. Adv. Sci.11 (38), e2404693. 10.1002/advs.202404693

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 101

  MaH.LuY.HuangZ.LongS.CaoJ.ZhangZ.et al (2022). ER-targeting cyanine dye as an NIR photoinducer to efficiently trigger photoimmunogenic cancer cell death. J. Am. Chem. Soc.144 (8), 3477–3486. 10.1021/jacs.1c11886

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 102

  MaoL.YinM.JiC.MaQ.XiaD.YangL. (2023). Targeted delivery of T-cell agonists for enhancing immunotherapy. J. Drug Deliv. Sci. Technol.89, 105074. 10.1016/j.jddst.2023.105074

  • CrossRef
  • Google Scholar

• 103

  MeyerH.KravicB. (2024). The endo-lysosomal damage response. Annu. Rev. Biochem.93 (1), 367–387. 10.1146/annurev-biochem-030222-102505

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 104

  MoanJ.BergK. (1991). The photodegradation of porphyrins in cells can be used to estimate the lifetime of singlet oxygen. Photochem. Photobiol.53 (4), 549–553. 10.1111/j.1751-1097.1991.tb03669.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 105

  NiedreM.PattersonM. S.WilsonB. C. (2002). Direct near-infrared luminescence detection of singlet oxygen generated by photodynamic therapy in cells in vitro and tissues in vivo. Photochem. Photobiol.75 (4), 382–391. 10.1562/0031-8655(2002)0750382DNILDO2.0.CO2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 106

  NiuN.YuY.ZhangZ.KangM.WangL.ZhaoZ.et al (2022). A cell membrane-targeting AIE photosensitizer as a necroptosis inducer for boosting cancer theranostics. Chem. Sci.13 (20), 5929–5937. 10.1039/D2SC01260J

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 107

  PanW. L.TanY.MengW.HuangN. H.ZhaoY. B.YuZ. Q.et al (2022a). Microenvironment-driven sequential ferroptosis, photodynamic therapy, and chemotherapy for targeted breast cancer therapy by a cancer-cell-membrane-coated nanoscale metal-organic framework. Biomaterials283, 121449. 10.1016/j.biomaterials.2022.121449

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 108

  PanY.TangW.FanW.ZhangJ.ChenX. (2022b). Development of nanotechnology-mediated precision radiotherapy for anti-metastasis and radioprotection. Chem. Soc. Reviews51 (23), 9759–9830. 10.1039/d1cs01145f

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 109

  PhamT. C.HoangT. T. H.TranD. N.KimG.NguyenT. V.PhamT. V.et al (2023). Imidazolium-based heavy-atom-free photosensitizer for nucleus-targeted fluorescence bioimaging and photodynamic therapy. ACS Appl. Mater. Interfaces15 (41), 47969–47977. 10.1021/acsami.3c10200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 110

  PlikusM. V.WangX.SinhaS.ForteE.ThompsonS. M.HerzogE. L.et al (2021). Fibroblasts: origins, definitions, and functions in health and disease. Cell184 (15), 3852–3872. 10.1016/j.cell.2021.06.024

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 111

  PopeL. E.DixonS. J. (2023). Regulation of ferroptosis by lipid metabolism. Trends Cell Biol.33 (12), 1077–1087. 10.1016/j.tcb.2023.05.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 112

  QianJ.LiaoG.ChenM.PengR. W.YanX.DuJ.et al (2024). Advancing cancer therapy: new frontiers in targeting DNA damage response. Front. Pharmacol.15, 1474337. 10.3389/fphar.2024.1474337

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 113

  QuH.ChenH.ChengW.PanY.DuanZ.WangY.et al (2023). Charge-reversible crosslinked nanoparticle for pro-apoptotic peptide delivery and synergistic photodynamic cancer therapy. Nano Res.16 (12), 13267–13282. 10.1007/s12274-023-5912-7

  • CrossRef
  • Google Scholar

• 114

  SabariB. R.Dall'AgneseA.YoungR. A. (2020). Biomolecular condensates in the nucleus. Trends Biochem. Sci.45 (11), 961–977. 10.1016/j.tibs.2020.06.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 115

  SettembreC.PereraR. M. (2024). Lysosomes as coordinators of cellular catabolism, metabolic signalling and organ physiology. Nat. Rev. Mol. Cell Biol.25 (3), 223–245. 10.1038/s41580-023-00676-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 116

  ShaoX.MengC.SongW.ZhangT.ChenQ. (2023). Subcellular visualization: organelle-specific targeted drug delivery and discovery. Adv. Drug Deliv. Rev.199, 114977. 10.1016/j.addr.2023.114977

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 117

  ShenW.HanG.YuL.YangS.LiX.ZhangW.et al (2022). Combined prussian blue nanozyme carriers improve photodynamic therapy and effective interruption of tumor metastasis. Int. J. Nanomedicine17 (null), 1397–1408. 10.2147/IJN.S359156

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 118

  ShenJ.QianN.XuG.DouX.AnY.YangC.et al (2024). IMT030122, A novel engineered EpCAM/CD3/4-1BB tri-specific antibody, enhances T-cell recruitment and demonstrates anti-tumor activity in mouse models of colorectal cancer. Int. Immunopharmacol.137, 112424. 10.1016/j.intimp.2024.112424

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 119

  ShiH.XiongC.ZhangL.CaoH.WangR.PanP.et al (2023). Light-triggered nitric oxide nanogenerator with high l-arginine loading for synergistic photodynamic/gas/photothermal therapy. Adv. Healthc. Mater.12 (20), 2300012. 10.1002/adhm.202300012

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 120

  ShiM.FuZ.PanW.WangK.LiuX.LiN.et al (2024). A golgi apparatus-targeted photothermal agent with protein anchoring for enhanced cancer photothermal therapy. Adv. Healthc. Mater.13 (17), e2303749. 10.1002/adhm.202303749

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 121

  ShigemitsuH.OhkuboK.SatoK.BunnoA.MoriT.OsakadaY.et al (2022). Fluorescein-based type I supramolecular photosensitizer via induction of charge separation by self-assembly. JACS Au2 (6), 1472–1478. 10.1021/jacsau.2c00243

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 122

  ŠlachtováV.ChovanecM.RahmM.VrabelM. (2023). Bioorthogonal chemistry in cellular organelles. Top. Curr. Chem.382 (1), 2. 10.1007/s41061-023-00446-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 123

  SongL.HaoY.WangC.HanY.ZhuY.FengL.et al (2022). Liposomal oxaliplatin prodrugs loaded with metformin potentiate immunotherapy for colorectal cancer. J. Control. Release350, 922–932. 10.1016/j.jconrel.2022.09.013

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 124

  SongW.YangH.WangY.ChenS.ZhongW.WangQ.et al (2024). Glutathione-sensitive photosensitizer-drug conjugates target the mitochondria to overcome multi-drug resistance in cancer. Adv. Sci.11 (30), e2307765. 10.1002/advs.202307765

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 125

  SoukarJ.PeppasN. A.GaharwarA. K. (2025). Organelle-targeting nanoparticles. Adv. Sci.12 (7), e2411720. 10.1002/advs.202411720

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 126

  SunB.Bte RahmatJ. N.ZhangY. (2022). Advanced techniques for performing photodynamic therapy in deep-seated tissues. Biomaterials291, 121875. 10.1016/j.biomaterials.2022.121875

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 127

  SunB.LiuJ.KimH. J.RahmatJ. N. B.NeohK. G.ZhangY. (2023a). Light-responsive smart nanocarriers for wirelessly controlled photodynamic therapy for prostate cancers. Acta Biomater.171, 553–564. 10.1016/j.actbio.2023.09.031

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 128

  SunH.XuJ.WangY.ShenS.XuX.ZhangL.et al (2023b). Bone microenvironment regulative hydrogels with ROS scavenging and prolonged oxygen-generating for enhancing bone repair. Bioact. Mater.24, 477–496. 10.1016/j.bioactmat.2022.12.021

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 129

  SunQ.YangJ.WuQ.ShenW.YangY.YinD. (2024). Targeting lysosome for enhanced cancer photodynamic/photothermal therapy in a “one stone two birds” pattern. ACS Appl. Mater. Interfaces16 (1), 127–141. 10.1021/acsami.3c13162

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 130

  SunS.ZhaoG.JiaM.JiangQ.LiS.WangH.et al (2024c). Stay in touch with the endoplasmic reticulum. Sci. China Life Sci.67 (2), 230–257. 10.1007/s11427-023-2443-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 131

  SunF.LiH.SunD.FuS.GuL.ShaoX.et al (2025). Single-cell omics: experimental workflow, data analyses and applications. Sci. China Life Sci.68 (1), 5–102. 10.1007/s11427-023-2561-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 132

  SweetM. J.RamnathD.SinghalA.KapetanovicR. (2025). Inducible antibacterial responses in macrophages. Nat. Rev. Immunol.25 (2), 92–107. 10.1038/s41577-024-01080-y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 133

  TanY.HuG.LiM.AnY.WangZ.LiuR.et al (2025). Two-photon photosensitizer for specific targeting and induction of tumor pyroptosis to elicit systemic immunity-boosting anti-tumor therapy. Biomaterials317, 123108. 10.1016/j.biomaterials.2025.123108

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 134

  TanakaT.WarnerB. M.MichaelD. G.NakamuraH.OdaniT.YinH.et al (2022). LAMP3 inhibits autophagy and contributes to cell death by lysosomal membrane permeabilization. Autophagy18 (7), 1629–1647. 10.1080/15548627.2021.1995150

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 135

  TangV. T.GinsburgD. (2023). Cargo selection in endoplasmic reticulum-to-golgi transport and relevant diseases. J. Clin. Investigation133 (1), e163838. 10.1172/jci163838

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 136

  TangY.BisoyiH. K.ChenX.-M.LiuZ.ChenX.ZhangS.et al (2023). Pyroptosis-mediated synergistic photodynamic and photothermal immunotherapy enabled by a tumor-membrane-targeted photosensitive dimer. Adv. Mater.35 (25), 2300232. 10.1002/adma.202300232

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 137

  TianH.LiW.WangG.TianY.YanJ.YuX.et al (2024). Metal-phenolic nanomaterial with organelle-level precision primes antitumor immunity via mtDNA-dependent cGAS-STING activation. Angew. Chem. Int. Ed.63 (50), e202411498. 10.1002/anie.202411498

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 138

  TongF.WangY.XuY.ZhouY.HeS.DuY.et al (2024). MMP-2-triggered, mitochondria-targeted PROTAC-PDT therapy of breast cancer and brain metastases inhibition. Nat. Commun.15 (1), 10382. 10.1038/s41467-024-54854-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 139

  VercellinoI.SazanovL. A. (2022). The assembly, regulation and function of the mitochondrial respiratory chain. Nat. Rev. Mol. Cell Biol.23 (2), 141–161. 10.1038/s41580-021-00415-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 140

  WanS.-S.ZhangL.ZhangX.-Z. (2019). An ATP-regulated ion transport nanosystem for homeostatic perturbation therapy and sensitizing photodynamic therapy by autophagy inhibition of tumors. ACS Central Sci.5 (2), 327–340. 10.1021/acscentsci.8b00822

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 141

  WangR.LiX.YoonJ. (2021). Organelle-targeted photosensitizers for precision photodynamic therapy. ACS Appl. Mater. Interfaces13 (17), 19543–19571. 10.1021/acsami.1c02019

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 142

  WangJ.YangB.LvC.ChenT.SunL.SunL.et al (2022a). Amino porphyrin-peptide assemblies induce ribosome damage and cancer stem cell inhibition for an enhanced photodynamic therapy. Biomaterials289, 121812. 10.1016/j.biomaterials.2022.121812

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 143

  WangM.WuM.LiuX.ShaoS.HuangJ.LiuB.et al (2022b). Pyroptosis remodeling tumor microenvironment to enhance pancreatic cancer immunotherapy driven by membrane anchoring photosensitizer. Adv. Sci.9 (29), e2202914. 10.1002/advs.202202914

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 144

  WangW.ZhuC.ZhangB.FengY.ZhangY.LiJ. (2023). Self-assembled nano-PROTAC enables near-infrared photodynamic proteolysis for cancer therapy. J. Am. Chem. Soc.145 (30), 16642–16649. 10.1021/jacs.3c04109

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 145

  WangB.ZhouH.ChenL.DingY.ZhangX.ChenH.et al (2024a). A mitochondria-targeted photosensitizer for combined pyroptosis and apoptosis with NIR-II imaging/photoacoustic imaging-guided phototherapy. Angew. Chem. Int. Ed.63 (39), e202408874. 10.1002/anie.202408874

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 146

  WangH.VantJ. W.ZhangA.SanchezR. G.WuY.MicouM. L.et al (2024b). Organization of a functional glycolytic metabolon on mitochondria for metabolic efficiency. Nat. Metab.6 (9), 1712–1735. 10.1038/s42255-024-01121-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 147

  WangP.BaiQ.LiuX.ZhaoM.ChenL.HuF.et al (2024c). Nucleus-targeting photosensitizers enhance neutrophil extracellular traps for efficient eradication of multidrug-resistant bacterial infections. Adv. Mater.36 (50), e2400304. 10.1002/adma.202400304

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 148

  WangX.WangX.LiY.QiZ. (2024d). COX-2 inhibition mediated aggregation-induced emission photosensitizer target the golgi apparatus for selective imaging of cancer cells and enhanced photodynamic therapy. Dyes Pigments222, 111897. 10.1016/j.dyepig.2023.111897

  • CrossRef
  • Google Scholar

• 149

  WeiX.SongM.JiangG.LiangM.ChenC.YangZ.et al (2022). Progress in advanced nanotherapeutics for enhanced photodynamic immunotherapy of tumor. Theranostics12 (12), 5272–5298. 10.7150/thno.73566

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 150

  WeigelA. V.ChangC. L.ShtengelG.XuC. S.HoffmanD. P.FreemanM.et al (2021). ER-to-Golgi protein delivery through an interwoven, tubular network extending from ER. Cell184 (9), 2412–2429.e16. 10.1016/j.cell.2021.03.035

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 151

  WenK.TanH.PengQ.ChenH.MaH.WangL.et al (2022). Achieving efficient NIR-II type-I photosensitizers for photodynamic/photothermal therapy upon regulating chalcogen elements. Adv. Mater.34 (7), e2108146. 10.1002/adma.202108146

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 152

  WuL.LiuJ.LiP.TangB.JamesT. D. (2021). Two-photon small-molecule fluorescence-based agents for sensing, imaging, and therapy within biological systems. Chem. Soc. Reviews50 (2), 702–734. 10.1039/d0cs00861c

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 153

  WuC.WangC.ZhangT.GaoG.WeiM.ChenY.et al (2022). Lysosome-targeted and fluorescence-turned “on” cytotoxicity induced by alkaline phosphatase-triggered self-assembly. Adv. Healthc. Mater.11 (1), 2101346. 10.1002/adhm.202101346

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 154

  WuD.HuangC.GuanK. (2024a). Mechanistic and therapeutic perspectives of miRNA-PTEN signaling axis in cancer therapy resistance. Biochem. Pharmacol.226, 116406. 10.1016/j.bcp.2024.116406

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 155

  WuY.LiY.YanN.HuangJ.LiX.ZhangK.et al (2024b). Nuclear-targeted chimeric peptide nanorods to amplify innate anti-tumor immunity through localized DNA damage and STING activation. J. Control. Release369, 531–544. 10.1016/j.jconrel.2024.04.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 156

  XiaD.ZhangX.HaoH.JiangW.ChenC.LiH.et al (2023). Strategies to prolong drug retention in solid tumors by aggregating Endo-CMC nanoparticles. J. Control. Release360, 705–717. 10.1016/j.jconrel.2023.07.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 157

  XieR.HuangH.ChenT.HuangX.ChenC. (2023a). Effectiveness and safety of pelareorep plus chemotherapy versus chemotherapy alone for advanced solid tumors: a meta-analysis. Front. Pharmacol.14, 1228225. 10.3389/fphar.2023.1228225

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 158

  XieZ.ZhaoM.YanC.KongW.LanF.Narengaowaet al (2023b). Cathepsin B in programmed cell death machinery: mechanisms of execution and regulatory pathways. Cell death Dis.14 (4), 255. 10.1038/s41419-023-05786-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 159

  XieX.SunT.PanH.JiD.XuZ.GaoG.et al (2024). Development of novel β-carboline/furylmalononitrile hybrids as type I/II photosensitizers with chemo-photodynamic therapy and minimal toxicity. Mol. Pharm.21 (7), 3553–3565. 10.1021/acs.molpharmaceut.4c00238

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 160

  XiongS.SongD.XiangY.LiY.ZhongY.LiH.et al (2020). Reactive oxygen species, not Ca2+, mediates methotrexate-induced autophagy and apoptosis in spermatocyte cell line. Basic Clin. Pharmacol. Toxicol.126 (2), 144–152. 10.1111/bcpt.13306

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 161

  XiongT.ChenY.LiM.ChenX.PengX. (2025). Recent progress of molecular design in organic type I photosensitizers. Small21 (22), e2501911. 10.1002/smll.202501911

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 162

  XuS.ZhuX.ZhangC.HuangW.ZhouY.YanD. (2018). Oxygen and Pt(II) self-generating conjugate for synergistic photo-chemo therapy of hypoxic tumor. Nat. Communications9 (1), 2053. 10.1038/s41467-018-04318-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 163

  XuY.WangS.ChenZ.HuR.ZhaoY.WangK.et al (2021). Nitric oxide release activated near-infrared photothermal agent for synergistic tumor treatment. Biomaterials276, 121017. 10.1016/j.biomaterials.2021.121017

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 164

  XuY.LiuR.YangH.QuS.QianL.DaiZ. (2022). Enhancing photodynamic therapy efficacy against cancer metastasis by ultrasound-mediated oxygen microbubble destruction to boost tumor-targeted delivery of oxygen and renal-clearable photosensitizer micelles. ACS Appl. Mater. Interfaces14 (22), 25197–25208. 10.1021/acsami.2c06655

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 165

  XuL.BaiE.ZhuY.QinJ.DuX.HuangH. (2023a). pH-responsive hydrogel as a potential oral delivery system of baicalin for prolonging gastroprotective activity. Pharmaceutics15 (1), 257. 10.3390/pharmaceutics15010257

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 166

  XuX.LiZ.ZhaoJ.LiuY.XuY.JiaY.et al (2023b). Catalase-conjugated rose bengal biological nanoparticles with mitochondrial selectivity toward photodynamic therapy. CCS Chem.5 (12), 2877–2887. 10.31635/ccschem.023.202202525

  • CrossRef
  • Google Scholar

• 167

  XuS.YanK. C.XuZ. H.WangY.JamesT. D. (2024). Fluorescent probes for targeting the golgi apparatus: design strategies and applications. Chem. Soc. Rev.53 (14), 7590–7631. 10.1039/d3cs00171g

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 168

  XuT.MaQ.ZhangC.HeX.WangQ.WuY.et al (2025a). A novel nanomedicine for osteosarcoma treatment: triggering ferroptosis through GSH depletion and inhibition for enhanced synergistic PDT/PTT therapy. J. Nanobiotechnology23 (1), 323. 10.1186/s12951-025-03380-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 169

  XuY.AnD.ZhangT.WuX.WangS.ShaoJ.et al (2025b). Mitochondrion-targeted type I photodynamic therapy for agonist independent cGAS-STING activation. Adv. Mater.37 (14), e2418894. 10.1002/adma.202418894

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 170

  XueM.DongL.ZhangH.LiY.QiuK.ZhaoZ.et al (2024). METTL16 promotes liver cancer stem cell self-renewal via controlling ribosome biogenesis and mRNA translation. J. Hematol. Oncol.17 (1), 7. 10.1186/s13045-024-01526-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 171

  YadavN.KumarS.MarloweT.ChaudharyA. K.KumarR.WangJ.et al (2015). Oxidative phosphorylation-dependent regulation of cancer cell apoptosis in response to anticancer agents. Cell Death Dis.6 (11), e1969. 10.1038/cddis.2015.305

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 172

  YanY.LiS.SuL.TangX.ChenX.GuX.et al (2024). Mitochondrial inhibitors: a new horizon in breast cancer therapy. Front. Pharmacol.15, 1421905. 10.3389/fphar.2024.1421905

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 173

  YangZ.WangJ.AiS.SunJ.MaiX.GuanW. (2019). Self-generating oxygen enhanced mitochondrion-targeted photodynamic therapy for tumor treatment with hypoxia scavenging. Theranostics9 (23), 6809–6823. 10.7150/thno.36988

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 174

  YangJ.GriffinA.QiangZ.RenJ. (2022). Organelle-targeted therapies: a comprehensive review on system design for enabling precision oncology. Signal Transduct. Target. Ther.7 (1), 379. 10.1038/s41392-022-01243-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 175

  YangF.YuW.YuQ.LiuX.LiuC.LuC.et al (2023a). Mitochondria-targeted nanosystem with reactive oxygen species-controlled release of CO to enhance photodynamic therapy of PCN-224 by sensitizing ferroptosis. Small19 (16), 2206124. 10.1002/smll.202206124

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 176

  YangL.ChenQ.GanS.HuangC.ZhangH.SunH. (2023b). Rational design of self-reporting photosensitizers for cell membrane-targeted photodynamic therapy. Anal. Chem.95 (32), 11988–11996. 10.1021/acs.analchem.3c01659

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 177

  YangL.MaH.LiuY.CaoR.ChenS.WangJ.et al (2023c). Nucleus-selective self-augmenting cascade nanoassemblies for targeted synergistic photo-chemo therapy of tumors. Chem. Commun.59 (73), 10940–10943. 10.1039/D3CC03331G

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 178

  YangW. W.RenZ. H.FengJ.LvZ. B.ChengX.ZhangJ.et al (2024). A deep-red emissive sulfur-doped double [7]helicene photosensitizer: synthesis, structure and chiral optical properties. Angew. Chem. Int. Ed.63 (45), e202412681. 10.1002/anie.202412681

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 179

  YaoR. Q.RenC.XiaZ. F.YaoY. M. (2021). Organelle-specific autophagy in inflammatory diseases: a potential therapeutic target underlying the quality control of multiple organelles. Autophagy17 (2), 385–401. 10.1080/15548627.2020.1725377

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 180

  YeZ.LiuJ.LiuY.ZhaoY.LiZ.XuB.et al (2024). Hybrid nanopotentiators with dual cascade amplification for glioma combined interventional therapy. J. Control. Release372, 95–112. 10.1016/j.jconrel.2024.06.016

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 181

  YingZ.YeN.MaQ.ChenF.LiN.ZhenX. (2023). Targeted to neuronal organelles for CNS drug development. Adv. Drug Deliv. Rev.200, 115025. 10.1016/j.addr.2023.115025

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 182

  YuQ.ShiH.DingZ.WangZ.YaoH.LinR. (2023a). The E3 ubiquitin ligase TRIM31 attenuates NLRP3 inflammasome activation in Helicobacter pylori-associated gastritis by regulating ROS and autophagy. Cell Commun. Signal.21 (1), 1. 10.1186/s12964-022-00954-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 183

  YuY.XiangL.ZhangX.ZhangL.NiZ.ZhuZ. H.et al (2023b). Pure organic AIE nanoscintillator for X-ray mediated type I and type II photodynamic therapy. Adv. Sci.10 (26), e2302395. 10.1002/advs.202302395

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 184

  YuL.LiuZ.XuW.JinK.LiuJ.ZhuX.et al (2024a). Towards overcoming obstacles of type II photodynamic therapy: endogenous production of light, photosensitizer, and oxygen. Acta Pharm. Sin. B14 (3), 1111–1131. 10.1016/j.apsb.2023.11.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 185

  YuY.LiuM.WangZ.LiuY.YaoM.WangL.et al (2024b). Identification of oxidative stress signatures of lung adenocarcinoma and prediction of patient prognosis or treatment response with single-cell RNA sequencing and bulk RNA sequencing data. Int. Immunopharmacol.137, 112495. 10.1016/j.intimp.2024.112495

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 186

  YuY.ZhangL.JiaH.JiC.LiuY.ZhaoZ.et al (2024c). Dual-mode reactive oxygen species-stimulated carbon monoxide release for synergistic photodynamic and gas tumor therapy. ACS Nano18 (45), 31286–31299. 10.1021/acsnano.4c10277

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 187

  ZengS.ChenJ.GaoR.ChenR.XueQ.RenY.et al (2024a). NIR-II photoacoustic imaging-guided oxygen delivery and controlled release improves photodynamic therapy for hepatocellular carcinoma. Adv. Mater.36 (4), e2308780. 10.1002/adma.202308780

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 188

  ZengS.WangY.ChenC.KimH.LiuX.JiangM.et al (2024b). An ER-targeted, viscosity-sensitive hemicyanine dye for the diagnosis of nonalcoholic fatty liver and photodynamic cancer therapy by activating pyroptosis pathway. Angew. Chem. Int. Ed.63 (9), e202316487. 10.1002/anie.202316487

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 189

  ZhangY.SwandaR. V.NieL.LiuX.WangC.LeeH.et al (2021a). mTORC1 couples cyst(e)ine availability with GPX4 protein synthesis and ferroptosis regulation. Nat. Commun.12 (1), 1589. 10.1038/s41467-021-21841-w

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 190

  ZhangZ.YueP.LuT.WangY.WeiY.WeiX. (2021b). Role of lysosomes in physiological activities, diseases, and therapy. J. Hematol. Oncol.14 (1), 79. 10.1186/s13045-021-01087-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 191

  ZhangM.LiuX.MaoY.HeY.XuJ.ZhengF.et al (2022a). Oxygen-generating hydrogels overcome tumor hypoxia to enhance photodynamic/gas synergistic therapy. ACS Appl. Mater. Interfaces14 (24), 27551–27563. 10.1021/acsami.2c02949

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 192

  ZhangM.ZhaoY.MaH.SunY.CaoJ. (2022b). How to improve photodynamic therapy-induced antitumor immunity for cancer treatment?Theranostics12 (10), 4629–4655. 10.7150/thno.72465

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 193

  ZhangT.LiuZ.TangW.ZhuD.LyuM.LamJ. W. Y.et al (2022c). Mitochondria-targeting type I AIE photosensitizer combined with H2S therapy: uninterrupted hydroxyl radical generation for enhancing tumor therapy. Nano Today46, 101620. 10.1016/j.nantod.2022.101620

  • CrossRef
  • Google Scholar

• 194

  ZhangX.WanJ.MoF.TangD.XiaoH.LiZ.et al (2022d). Targeting bone tumor and subcellular endoplasmic reticulum via near infrared II fluorescent polymer for photodynamic-immunotherapy to break the step-reduction delivery dilemma. Adv. Sci.9 (24), e2201819. 10.1002/advs.202201819

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 195

  ZhangH.ZhouP.JiangY.LiL.JuF.ChengQ.et al (2023a). Sustained-release esketamine based nanoparticle-hydrogel delivery system for neuropathic pain management. Int. J. Nanomedicine18 (null), 1131–1143. 10.2147/IJN.S400798

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 196

  ZhangT.YangX.OuX.LeeM. M. S.ZhangJ.XuC.et al (2023b). Tailoring the amphiphilic structure of zwitterionic AIE photosensitizers to boost antitumor immunity. Adv. Mater.35 (38), e2303186. 10.1002/adma.202303186

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 197

  ZhangX.YiC.ZhangL.ZhuX.HeY.LuH.et al (2023c). Size-optimized nuclear-targeting phototherapy enhances the type I interferon response for “cold” tumor immunotherapy. Acta Biomater.159, 338–352. 10.1016/j.actbio.2023.01.023

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 198

  ZhangY.JiaQ.NanF.WangJ.LiangK.LiJ.et al (2023d). Carbon dots nanophotosensitizers with tunable reactive oxygen species generation for mitochondrion-targeted type I/II photodynamic therapy. Biomaterials293, 121953. 10.1016/j.biomaterials.2022.121953

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 199

  ZhangQ.WangX.ChenJ.WuJ.ZhouM.XiaR.et al (2024). Recent progress of porphyrin metal–organic frameworks for combined photodynamic therapy and hypoxia-activated chemotherapy. Chem. Commun.60 (93), 13641–13652. 10.1039/D4CC04512B

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 200

  ZhangP.MukwayaV.GuanQ.XiongS.TianZ.Levi-KalismanY.et al (2025). Dextran-based nanodrugs with mitochondrial targeting/glutathione depleting synergy for enhanced photodynamic therapy. Carbohydr. Polymers348 (Pt A), 122854. 10.1016/j.carbpol.2024.122854

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 201

  ZhaoF.WangW.WuW. (2021). A novel ruthenium polypyridyl complex for the selective imaging and photodynamic targeting of the golgi apparatus. Dalton Trans.50 (10), 3536–3541. 10.1039/D1DT00216C

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 202

  ZhaoH.XuX.ZhouL.HuY.HuangY.NaritaA. (2022). Water-soluble nanoparticles with twisted double [7]carbohelicene for lysosome-targeted cancer photodynamic therapy. Small18 (1), e2105365. 10.1002/smll.202105365

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 203

  ZhaoY.HuangT.WangS.YaoS.HuQ.WanX.et al (2023). Manganese oxide-modified bismuth oxychloride piezoelectric nanoplatform with multiple enzyme-like activities for cancer sonodynamic therapy. J. Colloid Interface Sci.640, 839–850. 10.1016/j.jcis.2023.03.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 204

  ZhaoY.LiuZ.DengK.QuH.ZhangQ.ZhouP.et al (2024). Identification of TAP1 as a T-cell related therapeutic target in gastric cancer by mediating oxalipliatin-related synergistic enhancement of immunotherapy. Int. Immunopharmacol.132, 111998. 10.1016/j.intimp.2024.111998

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 205

  ZhenS.XuZ.SuoM.ZhangT.LyuM.LiT.et al (2025). NIR-II AIE liposomes for boosting type-I photodynamic and mild-temperature photothermal therapy in breast cancer treatment. Adv. Mater.37 (3), e2411133. 10.1002/adma.202411133

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 206

  ZhengX.JinY.LiuX.LiuT.WangW.YuH. (2021a). Photoactivatable nanogenerators of reactive species for cancer therapy. Bioact. Mater.6 (12), 4301–4318. 10.1016/j.bioactmat.2021.04.030

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 207

  ZhengZ.DengW.BaiY.MiaoR.MeiS.ZhangZ.et al (2021b). The lysosomal rag-ragulator complex licenses RIPK1 and caspase-8-mediated pyroptosis by yersinia. Science372 (6549), eabg0269. 10.1126/science.abg0269

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 208

  ZhouL.WeiF.XiangJ.LiH.LiC.ZhangP.et al (2020). Enhancing the ROS generation ability of a rhodamine-decorated iridium(iii) complex by ligand regulation for endoplasmic reticulum-targeted photodynamic therapy. Chem. Sci.11 (44), 12212–12220. 10.1039/D0SC04751A

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 209

  ZhuS.-y.YaoR.-q.LiY.-x.ZhaoP.-y.RenC.DuX.-h.et al (2020). Lysosomal quality control of cell fate: a novel therapeutic target for human diseases. Cell Death Dis.11 (9), 817. 10.1038/s41419-020-03032-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 210

  ZhuZ.WangQ.LiaoH.LiuM.LiuZ.ZhangY.et al (2021). Trapping endoplasmic reticulum with amphiphilic AIE-active sensor via specific interaction of ATP-sensitive potassium (K(ATP)). Natl. Sci. Rev.8 (6), nwaa198. 10.1093/nsr/nwaa198

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 211

  ZhuJ.JiaoA.LiQ.LvX.WangX.SongX.et al (2022). Mitochondrial Ca(2+)-overloading by oxygen/glutathione depletion-boosted photodynamic therapy based on a CaCO(3) nanoplatform for tumor synergistic therapy. Acta Biomater.137, 252–261. 10.1016/j.actbio.2021.10.016

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 212

  ZhuY.GongP.WangJ.ChengJ.WangW.CaiH.et al (2023). Amplification of lipid peroxidation by regulating cell membrane unsaturation to enhance chemodynamic therapy. Angew. Chem. Int. Ed.62 (12), e202218407. 10.1002/anie.202218407

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 213

  ZhuX.ShiZ.MaoY.LächeltU.HuangR. (2024a). Cell membrane perforation: patterns, mechanisms and functions. Small20 (24), e2310605. 10.1002/smll.202310605

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 214

  ZhuY.WangX.FengL.ZhaoR.YuC.LiuY.et al (2024b). Intermetallics triggering pyroptosis and disulfidptosis in cancer cells promote anti-tumor immunity. Nat. Commu.15 (1), 8696. 10.1038/s41467-024-53135-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 215

  ZhuL.HuJ.WuX.ZhangJ.XuX.HuangX.et al (2025). Programmed enhancement of endogenous iron-mediated lysosomal membrane permeabilization for tumor ferroptosis/pyroptosis dual-induction. Nat. Commu.16 (1), 3017. 10.1038/s41467-025-58124-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 216

  ZhuangZ.DaiJ.YuM.LiJ.ShenP.HuR.et al (2020). Type I photosensitizers based on phosphindole oxide for photodynamic therapy: apoptosis and autophagy induced by endoplasmic reticulum stress. Chem. Sci.11 (13), 3405–3417. 10.1039/D0SC00785D

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 217

  ZhuangJ.WangB.ChenH.ZhangK.LiN.ZhaoN.et al (2023). Efficient NIR-II type-I AIE photosensitizer for mitochondria-targeted photodynamic therapy through synergistic apoptosis-ferroptosis. ACS Nano17 (10), 9110–9125. 10.1021/acsnano.2c12319

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 218

  ZhuangJ.LiuS.LiB.LiZ.WuC.XuD.et al (2025). Electron transfer mediator modulates type II porphyrin-based metal-organic framework photosensitizers for type I photodynamic therapy. Angew. Chem. Int. Ed.64 (9), e202420643. 10.1002/anie.202420643

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 219

  ZimmermannJ. A.LuchtK.StecherM.BadhanC.GlaserK. M.EppleM. W.et al (2024). Functional multi-organelle units control inflammatory lipid metabolism of macrophages. Nat. Cell Biol.26 (8), 1261–1273. 10.1038/s41556-024-01457-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 220

  ZouY.ChenJ.LuoX.QuY.ZhouM.XiaR.et al (2024a). Porphyrin-engineered nanoscale metal-organic frameworks: enhancing photodynamic therapy and ferroptosis in oncology. Front. Pharmacol.15, 1481168. 10.3389/fphar.2024.1481168

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 221

  ZouY.WuJ.ZhangQ.ChenJ.LuoX.QuY.et al (2024b). Recent advances in cell membrane-coated porphyrin-based nanoscale MOFs for enhanced photodynamic therapy. Front. Pharmacol.15, 1505212–2024. 10.3389/fphar.2024.1505212

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 222

  ZouY.ChenJ.QuY.LuoX.WangW.ZhengX. (2025a). Evolution of nMOFs in photodynamic therapy: from porphyrins to chlorins and bacteriochlorins for better efficacy. Front. Pharmacol.16, 1533040. 10.3389/fphar.2025.1533040

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 223

  ZouY.ZhangQ.ChenJ.WangW.ZhengX. (2025b). Metal-organic frameworks-loaded indocyanine green for enhanced phototherapy: a comprehensive review. Front. Bioeng. Biotechnol.13, 1601476. 10.3389/fbioe.2025.1601476

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 224

  ZuoL.NieW.YuS.ZhuangW.WuG.LiuH.et al (2021). Smart tumor-cell-derived microparticles provide on-demand photosensitizer synthesis and hypoxia relief for photodynamic therapy. Angew. Chem. Int. Ed.60 (48), 25365–25371. 10.1002/anie.202109258

  • Pubmed Abstract
  • CrossRef
  • Google Scholar