Abstract
Liver diseases represent a significant global health challenge, affecting millions of lives annually. The advent of nanoparticle (NP) technologies has introduced promising therapeutic strategies for addressing liver diseases. Given the liver’s pivotal role in detoxification and the inherent ability to interact with circulating NPs, it emerges as an ideal target for NP-mediated therapies. Upon systemic administration, NPs predominantly accumulate within the liver, where they are uptaken and internalized by hepatic macrophages, sinusoidal endothelial cells, and hepatocytes. This natural tropism of NPs toward the liver highlights their potential for targeted liver disease management. This review describes the physiological conditions of the hepatic sinusoids and elucidates the interactions between various hepatic cells and NPs. A thorough understanding of these physiological mechanisms is essential for optimizing liver-targeted NP delivery systems, thereby improving NP accumulation at pathological sites. The development of liver-targeted NPs technologies holds immense promise for both the diagnosis and treatment of liver diseases.
1 Introduction
Liver diseases are widely prevalent all over the world, affecting individuals in both low-income countries and high-income countries (; ). Annually, approximately two million lives are lost due to liver related diseases, one million attributed to cirrhosis, and one million attributed to viral hepatitis and hepatocellular carcinoma (HCC) (Yeo et al., 2024; ). The spectrum of liver diseases encompasses acute liver failure, various forms of hepatitis (viral, alcoholic, fatty, metabolic), cirrhosis, and HCC (). These conditions not only inflict direct damage upon the liver parenchyma but also disrupt hepatic metabolism of carbohydrates, lipids, and proteins, leading to systemic metabolic derangements characteristic of liver disease patients (). Consequently, the impaired hepatic function significantly hampers the uptake and utilization of numerous drugs, posing substantial challenges to the development of effective liver-targeted therapies ().
In recent years, nanoparticle (NP) technologies have emerged as a groundbreaking frontier in medical research, demonstrating remarkable progress across diverse therapeutic domains (; ). NPs delivery systems hold the potential to revolutionize drug distribution within the body by prolonging systemic circulation times and facilitating targeted delivery to pathological sites (Yang L. et al., 2024). NPs encompasses five groups based on the nanoconstructs, including inorganic metal NPs, carbon-based NPs, lipid NPs, polymeric NPs, and nucleic acid NPs (Zhang JA. et al., 2024). Through strategic modifications, these NPs can be tailored for organ-specific targeting, thereby enhancing therapeutic efficacy while minimizing off-target effects. The escalating demand for advanced therapies has propelled several NP formulations into clinical trials, heralding a new era in precision medicine (; ).
NPs hepatic uptake is achieved through passive or active means. Passive uptake is non-specific, primarily mediated by the mononuclear phagocyte system (MPS) capturing unmodified particles. Active targeting enhances specificity by decorating nanomaterials with targeting moieties (e.g., antibodies, peptides) that bind to unique receptors on particular liver cells, such as hepatocytes, reducing off-target sequestration and improving delivery efficiency (). However, a significant limitation of NP-based therapies lies in their rapid clearance by MPS, which constitutes a major barrier to effective drug delivery (). The MPS, primarily composed of macrophages residing in the liver (Kupffer cells) and spleen, functions as the body’s filtration system, actively sequestering and internalizing circulating NPs (Zelepukin et al., 2024). Studies indicate that nearly 85% of liver macrophages and 25% of splenic macrophages will accumulate NPs, underscoring the liver’s pivotal role in NP biodistribution (). Meanwhile, this phenomenon also positions the liver as an optimal target organ for nanotherapeutics, given its inherent capacity to accumulate NPs. By integrating passive hepatic uptake mechanisms with active targeting strategies, the therapeutic potential of NPs in managing liver diseases can be substantially augmented ().
This review aims to provide a comprehensive overview of NP-mediated targeting strategies and their applications in the treatment of liver diseases. We commence by elucidating the microanatomical features of the liver and the implications of hepatic sinusoidal architecture on NP accumulation and clearance. Subsequently, we delve into the impact of NP characteristics on their biodistribution and liver-targeting efficiency. Lastly, we highlight the therapeutic prospects of NPs in addressing acute liver failure (ALF), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, and HCC, emphasizing the transformative potential of nanotechnology in advancing liver disease management.
2 The accumulation of NPs in the liver
2.1 Hepatic sinusoidal architecture makes liver an ideal organ for NPs accumulation
The liver, being one of the most vital organs in the human body, plays a crucial role in metabolic processes, detoxification, and protein synthesis. Liver receives a substantial blood supply, accounting for approximately 1.5 L per minute, which is among the highest perfusion rates in the body (; ). This blood is delivered through two primary vessels: the hepatic artery and the portal vein, contributing 30% and 70% of the total hepatic blood flow, respectively (). The hepatic artery supplies oxygenated blood, while the portal vein delivers nutrient-rich blood from the gastrointestinal tract. Within the hepatic sinusoids, blood from these vessels mixes, undergoes metabolic exchange, and is subsequently drained via the central veins. Notably, despite the rapid flow in the afferent vessels, the blood velocity within the sinusoids dramatically decreases to 1/1000th that of the portal vein, creating a low-velocity environment conducive to NP adhesion and retention ().
At the cellular level, the liver comprises parenchymal cells (hepatocytes, constituting 60% of all liver cells) and non-parenchymal cells (40% of all liver cells), including liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), and Kupffer cells (KCs) (Figure 1) (). Hepatocytes are organized in single-cell cords towards the center of the lobule, making contact with the sinusoidal blood vessels (). LSECs and hepatocytes are separated by a region known as the space of Disse. These spaces facilitate the exchange of small molecules and nutrients between blood and hepatocytes. LSECs form a fenestrated barrier with pores ranging from 50 nm to 200 nm in diameter, functioning akin to a selective filter that promotes efficient uptake of substances by hepatocytes (). HSCs, rich in lipid droplets and vitamin A, contribute to the extracellular matrix formation. KCs, dispersed among LSECs, act as the liver’s resident macrophages, engulfing foreign particles and debris from the bloodstream ().
FIGURE 1
When NPs enter the hepatic sinusoids, their interaction with this intricate microenvironment significantly influences their biodistribution and fate. Due to the slow blood flow, a substantial portion of NPs adheres to the LSECs, facilitating their uptake by KCs (). However, not all NPs are cleared in this manner; a fraction evades phagocytic surveillance and is internalized by LSECs. NPs larger than 200 nm are shunted into the systemic circulation and eventually sequestered by the spleen, whereas smaller NPs (<200 nm) penetrate deeper into the liver parenchyma, interacting directly with hepatocytes and HSCs (; ).
2.2 Route of NPs administration promotes the accumulation of NPs in the liver
The route of administration plays a crucial role in determining the biodistribution and accumulation of NPs within the body, with the liver being a primary target organ for NPs accumulation due to its extensive blood supply and unique sinusoidal architecture (Xu et al., 2023). The most common routes of administration in clinical practice and animal models include oral, intravenous, intramuscular, and intraperitoneal injections (). Each route has distinct advantages and challenges that influence the efficiency of NPs delivery and subsequent hepatic accumulation.
Oral administration is often preferred due to its convenience and high patient compliance. However, this route presents significant challenges as NPs must navigate the complex gastrointestinal environment (; ). Gastric juices, pancreatic enzymes, intestinal fluids, and bile can all contribute to the unexpected loss of NPs (). Additionally, the penetrability of NPs through the mucus layer and intestinal epithelium is vital for their absorption and bioavailability (Xu et al., 2024). Furthermore, the gastrointestinal tract is rich in macrophages and dendritic cells capable of clearing substantial quantities of NPs (; ). Despite these obstacles, an adequate dose of NPs can evade these defenses and enter systemic circulation.
In contrast, intravenous, intramuscular, and intraperitoneal injections bypass the digestive tract, thereby overcoming some of the barriers associated with oral administration and potentially enhancing bioavailability. Intravenous injection provides the most direct and highest initial hepatic exposure, as NPs enter the systemic circulation directly, bypassing other absorption barriers and allowing immediate interaction with liver sinusoids and Kupffer cells. However, these routes may suffer from reduced practicality due to factors such as invasiveness, potential for localized side effects, and the need for specialized administration procedures ().
Regardless of the administration route, NPs ultimately enter systemic circulation. Venous blood from the head, neck, and upper limbs returns to the heart before entering the portal system. Blood from the lower limbs enters the systemic circulation via the inferior vena cava (; ). Given the liver’s rich blood supply, NPs inevitably pass through the liver where they undergo metabolism. This physiological process highlights the liver’s central role in NP clearance and underscores the importance of understanding how different administration routes impact NP biodistribution and hepatic accumulation.
2.3 The interactions of NPs with various hepatic cells in the liver disease
The innovative NPs are designed to interact specifically with the diverse cellular populations of the liver—including KCs, HSCs, LSECs, and hepatocytes—each playing distinct roles in disease progression and treatment response. Several NPs-based formulations have already progressed to clinical trials, demonstrating promising potential for enhancing drug delivery, improving therapeutic efficacy, and reducing systemic side effects (Table 1). This section summarizes the mechanisms through which NPs interact with different hepatic cell types in both healthy and diseased microenvironments, with particular emphasis on those systems that have reached clinical-stage development, thereby bridging foundational research with translational applications.
TABLE 1
| Nanoparticle systems | NPs formulation | Delivered drugs | Stage | References |
|---|---|---|---|---|
| Lipid-based NPs | VA-liposomes | Imatinib | Phase Ⅱ | |
| Lipid-based NPs | VA-liposomes | Valsartan | Phase Ⅱ | |
| Lipid-based NPs | pPB-modified liposomes | Recombinant human TRAIL | Phase Ⅲ | |
| Polymer-based NPs | Cationic nanohydrogel particles | siRNA | Phase Ⅲ | |
| Polymer-based NPs | Ketal cross-linked cationic nanohydrogel | Anti-col1α1 siRNA | Phase Ⅱ | |
| Polymer-based NPs | PLGA | phyllanthin | Phase Ⅱ | Zhang et al. (2018) |
| Polymer-based NPs | PEG-PLGA/PLGA NPs | sorafenib | Phase Ⅱ | |
| Inorganic NPs | Mesoporous silica NPs | siTnC | Phase Ⅲ | |
| Inorganic NPs | PEG-AuNPs | hesperetin | Phase Ⅱ | |
| Inorganic NPs | AuNPs and SiNPs | NO donors | Phase Ⅱ | |
| Inorganic NPs | PtNPs | Curcumin | Phase Ⅱ | |
| Inorganic NPs | Calcium phosphate NPs (CaP@BSA NPs) | TSG-6 | Phase Ⅱ |
Nanoparticle systems for liver disease in clinical trials or commercialized.
Upon entering the hepatic sinusoids, NPs first encounter KCs, which constitute a vital component of the MPS, accounting for approximately 80% of the body’s macrophages (). KCs play an essential role in liver immune regulation and maintaining immunological homeostasis. KCs are categorized into two distinct subpopulations based on their functional roles and secretion profiles: M1 and M2 macrophages (). M1 macrophages, activated by lipopolyscharide (LPS) and interferon-gamma (IFN-γ), secrete high levels of interleukin-2 (IL-2) and lower levels of interleukin-10 (IL-10), primarily promoting inflammation, bactericidal activity, and phagocytosis (Wang R. et al., 2024). Conversely, M2 macrophages, activated by interleukin-4 (IL-4), predominantly secrete anti-inflammatory cytokines such as IL-10, thereby suppressing local inflammatory responses (). Numerous studies have demonstrated that NPs can facilitate the conversion of M1 to M2 macrophages through drug delivery, mitigating macrophage-driven inflammatory responses and thus alleviating liver disease (Figure 2) (; Zhang W. et al., 2024; ). Additionally, KCs express high levels of pattern recognition receptors, such as mannose receptors. NPs modified with ligands targeting these receptors can achieve specific localization to KCs, enhancing their therapeutic efficacy ().
FIGURE 2
HSCs primarily function in lipid and retinol storage. In healthy livers, HSCs remain quiescent. However, under pathological conditions, various inflammatory insults can activate HSCs, leading to their differentiation into fibroblasts (). Prolonged chronic injury results in the activation and proliferation of HSCs, which fill the Disse space, causing hepatic fibrosis (; ). This pathological process significantly impedes the entry of NPs into the liver parenchyma. Therefore, mitigating HSCs activation to alleviate fibrosis represents an effective therapeutic strategy. Studies have utilized HSCs membrane-derived biofilms to encapsulate drugs into uniform NPs. By leveraging the principle of homologous targeting, these NPs deliver drugs specifically to HSCs, thereby addressing hepatic fibrosis (). Another approach involves modifying NPs with vitamin A, capitalizing on the characteristic ability of HSCs to store vitamin A to target drug delivery directly to these cells ().
LSECs, uniquely positioned at the interface of blood and hepatocytes, play a pivotal role in regulating the passage of substances into the liver parenchyma (). Central to understanding NP-LSEC interactions is the concept of liver fenestrations. The diameter of these fenestrations imposes physical constraints on the entry of NPs into the liver, necessitating meticulous consideration of NP size during the design phase (). By tailoring NP dimensions to align with the specific fenestration sizes of target species or patient populations, researchers can optimize liver targeting efficiency, thereby enhancing therapeutic outcomes. Beyond their role in filtration, LSECs serve as crucial antigen-presenting cells, actively participating in immune surveillance within the liver (). Their high expression of mannose receptors underscores their potential as targets for immunomodulatory strategies (). NPs engineered to specifically bind mannose receptors on LSECs could facilitate targeted delivery of therapeutic agents, thereby enhancing localized treatment effects while minimizing systemic side effects. Recent studies have illuminated the charge-selective properties of LSECs, revealing a preferential uptake of negatively charged NPs compared to their positively charged counterparts (Yap et al., 2020). Capitalizing on this observation, researchers have designed charge-selective NPs that exploit these preferences to achieve heightened liver accumulation. Charge-selective NPs have been shown to effectively suppress endothelial growth factor receptor-2 (EGFR-2) expression in LSECs, a pivotal step in inhibiting angiogenesis and tumor progression in mouse HCC model (Yazdi et al., 2024).
Hepatocytes, being the most abundant cell type in the liver and central to its functional execution, are prime targets for NP-mediated therapeutic interventions (Zhao et al., 2024). One of the prominent strategies for targeting hepatocytes involves exploiting the high concentration of digestive enzymes within these cells. Many studies have demonstrated that targeting specific digestive enzyme receptors on hepatocytes to achieve efficient delivery of therapeutic agents. This approach leverages the natural biological processes of the liver to enhance the specificity and effectiveness of drug delivery systems (Zhao et al., 2024; Zhang et al., 2024c; ). Among the various targeting ligands, N-acetylgalactosamine (GalNAc) and apolipoprotein E (ApoE) stand out for their exceptional affinity and functionality in hepatocyte targeting. GalNAc binds with high specificity to the ASGPR expressed on the surface of hepatocytes (). This interaction facilitates the internalization of NPs, making it an attractive strategy for delivering drugs or genes directly to hepatocytes. By conjugating GalNAc to the surface of NPs or therapeutic cargos, researchers can significantly enhance the uptake efficiency and specificity towards hepatocytes, thereby improving therapeutic outcomes (). Similarly, ApoE, a major apolipoprotein found in chylomicrons, plays a crucial role in lipid metabolism and is readily taken up by hepatocytes. Anchoring ApoE onto NP surfaces has been shown to enhance the targeting efficiency of NPs to hepatocytes, offering another viable strategy for liver-specific drug delivery (). This approach not only improves the bioavailability of drugs at the target site but also minimizes systemic side effects by reducing off-target accumulation ().
3 Factors affecting the biodistribution of NPs
The biodistribution of NPs after intravenous, intramuscular, or intraperitoneal injection is a critical determinant of their therapeutic efficacy and safety. Several key physicochemical properties of NPs significantly impact their ability to be taken up by the liver (Figure 3). The size of NPs is a primary determinant of their fate within the body (Zaleski et al., 2024). Larger NPs often face difficulties in crossing the fenestrations of LSECs, whereas smaller NPs can more readily pass through these openings. Additionally, the shape of NPs plays a crucial role, spherical NPs typically exhibit different uptake kinetics compared to rod-shaped or other anisotropic forms (Yan et al., 2024). Furthermore, the surface charge of NPs also affects their interaction with cellular membranes and their subsequent internalization by hepatocytes (). The surface modification of NPs is another critical factor influencing their hepatic uptake. Functional groups or ligands attached to the NP surface can enhance or inhibit interactions with specific cell types within the liver (). The surface chemistry of NPs, modified with specific functional groups or targeting ligands, profoundly influences their interactions with biological systems. For instance, the incorporation of polyethylene glycol is a common strategy to impart “stealth” properties and prolong circulation time by reducing opsonization and mononuclear phagocyte system uptake (). The material composition of NPs, including their hardness and porosity, can also influence their absorption and distribution within the liver. Stiffer materials may resist deformation during passage through the narrow fenestrations of while porous NPs could allow for better interaction with cellular components (). Understanding the factors that influence how NPs are taken up and utilized by the liver is essential for optimizing their design and application in liver-targeted therapies.
FIGURE 3
3.1 Size
The size of NPs is a critical determinant of their administration routes and biodistribution within the body. The clearance mechanisms in the bloodstream play a significant role in determining the fate of NPs based on their size. Larger NPs, typically those exceeding 500 nm in diameter, are prone to rapid clearance by macrophages in the blood. This clearance process limits their circulation time and availability for targeted delivery, making them less suitable for systemic applications (). In contrast, micrometer-sized NPs (>1 μm) are often utilized in pulmonary drug delivery systems, particularly through nebulization (Witten et al., 2024; ). These larger particles are generally not recommended for intravenous administration due to their inability to navigate the intricate network of capillaries and the risk of embolism. At the other end of the spectrum, extremely small NPs (<50 nm) exhibit enhanced tissue penetration capabilities. Their small size allows them to distribute throughout the body more effectively but also increases the likelihood of uptake by lymphatic tissues (; ). Additionally, these tiny NPs can be filtered and eliminated by the kidneys. The glomerular endothelial cells in the kidneys have fenestrations smaller than 10 nm, which means that NPs below this size threshold will be rapidly cleared from the bloodstream via renal excretion (; ). Consequently, ultra-small NPs have very short circulation times, often being completely excreted within a few hours after administration.
Given these considerations, the ideal size range for NPs intended for liver targeting falls between 50 nm and 200 nm. They are large enough to avoid immediate renal excretion, thereby prolonging their circulation in the bloodstream (). This extended half-life is crucial for allowing sufficient time for the NPs to extravasate and accumulate within the liver (). More specifically, the fenestrated endothelial lining of the liver sinusoids contains pores ranging from 50 to 150 nm in diameter. NPs under 200 nm can efficiently traverse these fenestrations, gaining direct access to the space of Disse and subsequently to the underlying hepatocytes. This process is fundamental for passive targeting and enhanced permeability.
Furthermore, this size range is highly compatible with various active targeting strategies. For instance, NPs can be functionalized with ligands such as galactose to target the asialoglycoprotein receptor (ASGPR) abundantly expressed on hepatocytes (). The 50–200 nm size ensures that these ligand-decorated particles maintain favorable pharmacokinetics and biodistribution, maximizing receptor-mediated internalization while minimizing non-specific off-target accumulation (). In summary, the 50–200 nm size range strikes a critical balance between prolonged circulation, efficient hepatic penetration, and enhanced cellular uptake, making it a cornerstone rationale in the design of liver-targeted nanotherapeutics.
3.2 Shape
The shape of NPs significantly influences their biodistribution and cellular uptake, particularly within the liver. Among various shapes such as cubes, rods, spheres, and stars, spherical NPs are particularly advantageous for cellular uptake, especially under conditions of slow blood flow typical in hepatic sinusoids (). In turbulent blood flow, spherical NPs experience distinct forces compared to other shapes. They tend to be compressed by the walls of smaller radius vessels and subsequently move towards larger radius vessels. This movement facilitates their eventual internalization by endothelial or other cell types lining these vessels (). In contrast, non-spherical NPs, such as nanorods or cubic structures, exhibit markedly different behaviors in turbulent flow. Their anisotropic shapes lead to complex rotational dynamics and increased susceptibility to collisions with vascular walls. Rather than undergoing efficient cellular uptake, these particles often enter a sliding motion along the vessel centerline, reducing their contact time with the endothelial surface and diminishing their likelihood of being engulfed via endocytic pathways (; ). This hydrodynamic profiling underscores the importance of shape uniformity in minimizing off-target movement and maximizing hepatic accumulation.
Furthermore, the preference for spherical NPs is reinforced by biological interactions at the cellular level. Their symmetrical shape allows for more uniform ligand distribution, which is crucial for receptor-mediated uptake mechanisms prevalent in liver cells (; ). The combination of favorable hemodynamic properties and optimized surface presentation makes spherical NPs particularly advantageous for navigating the liver’s intricate vasculature and achieving efficient intracellular delivery (; Yue et al., 2023). Thus, while novel shapes may offer unique mechanical or optical properties, spherical nanoparticles remain the gold standard for hepatic targeting due to their enhanced hydrodynamic performance and cellular engagement in slow-flow systems ().
This hydrodynamic effect is exacerbated in diseased states such as hypertension and atherosclerosis, where increased turbulence and narrowing of blood vessels are common (; ). The altered blood flow patterns in these conditions can further hinder the effective delivery and uptake of non-spherical NPs, highlighting the importance of considering NP shape in the design of targeted therapies.
3.3 Charge
The surface charge of NPs is another critical factor influencing their biodistribution and tissue-specific accumulation. Here, we explore how the presence of surface charges affects the apparent acid dissociation constant (pKa) of NPs, which in turn influences their aggregation properties in different tissues. Research has demonstrated that the liver preferentially accumulates NPs with a pKa between 6 and 7. Conversely, lungs exhibit a higher affinity for NPs with a pKa greater than 9. NPs with a pKa less than 6 are more readily taken up by the spleen. These findings suggest that the pKa of NPs can be strategically manipulated to enhance their uptake by specific organs (; ).
One sophisticated strategy to engineer NPs for improved hepatic accumulation involves the deliberate modulation of their surface charge through the conjugation of specific biological proteins. A prominent example is the use of ApoE, a protein that naturally carries a net negative charge and plays a key role in lipid metabolism and receptor-mediated endocytosis. When ApoE is adsorbed or covalently attached to the surface of synthetic NPs that are typically engineered to possess an initial positive charge, it fundamentally alters their electrostatic profile. This conjugation effectively neutralizes the highly positive surface and confers a negatively charged, biomimetic corona. This newly acquired negative surface characteristic is critically important for targeting LSECs. These resident liver cells exhibit a well-documented affinity for and efficiently scavenge negatively charged macromolecules and particulates from the circulation, a process driven by specialized scavenger receptors.
Beyond merely facilitating initial LSEC recognition and acceptance, the ApoE corona acts as a sophisticated biological targeting ligand. It enables the NPs to hijack endogenous metabolic pathways, particularly those involving the LDL receptor family abundantly expressed on the surface of hepatocytes. Consequently, ApoE-functionalized NPs benefit from a dual-targeting mechanism: initial sequestration by LSECs due to charge preference, followed by enhanced, receptor-mediated uptake into hepatocytes. Empirical evidence strongly supports the efficacy of this approach. For instance, comprehensive studies utilizing gold nanoparticles with a diameter of approximately 80 nm—a size optimized for traversing hepatic sinusoidal fenestrations—demonstrate a dramatic increase in liver accumulation when coated with ApoE. Quantitative biodistribution analyses reveal that these bio-functionalized NPs achieve significantly higher concentrations within liver tissue compared to their uncoated, positively charged counterparts, which are more prone to opsonization and clearance by the immune system or accumulation in off-target organs (; ). Thus, ApoE modification represents a powerful protein-based strategy to leverage the liver’s inherent cellular and molecular machinery for superior nanoparticle delivery.
One approach to designing NPs for enhanced liver uptake involves modifying their surface charge through conjugation with proteins. For instance, ApoE, a protein commonly associated with negative charges, can be used to modify positively charged NPs. This modification alters the overall charge characteristics of the NPs, making them more attractive to LSECs, which have a preference for negatively charged particles. Furthermore, ApoE not only facilitates the acceptance of NPs by LSECs but also enhances their uptake by hepatocytes. Studies have shown that gold NPs coated with ApoE and measuring 80 nm in diameter achieve significantly higher concentrations within the liver compared to uncoated NPs.
3.4 Surface modification
Surface modification of NPs is a common strategy for liver targeting, serving two primary purposes: enhancing uptake by specific cells within the liver and evading rapid clearance by the body (Yang M. et al., 2024). One effective approach to prevent rapid uptake and clearance of NPs is surface modification with polyethylene glycol (PEG). PEGylation significantly increases the hydrophobicity of NPs, preventing their recognition and subsequent clearance by blood macrophages. This modification extends the half-life of NPs in the bloodstream, thereby enhancing their circulation time and potential for targeted delivery (; Zheng et al., 2023). Another method to avoid rapid NP clearance involves coating NPs with a biomimetic membrane. Coating nanoparticles with biomimetic membranes—such as those derived from red blood cells, platelets, or leukocytes—has emerged as a powerful strategy to enhance biocompatibility and impart advanced targeting capabilities. The use of such membranes can mimic endogenous substances, signaling to cells that the NPs are non-threatening and thus less likely to be cleared by immune responses. This biomembrane coating provides a form of immunological camouflage, facilitating longer systemic circulation of NPs (; ). Conjugating antibodies to the NP surface is another effective strategy for promoting targeted delivery. For instance, synthesizing an antibody targeting epidermal growth factor receptor-2 (HER2) and anchoring it to NPs allows for specific targeting of HER2-positive tumor cells. This targeted approach enhances the selective accumulation of NPs at the desired site, improving therapeutic efficacy while minimizing off-target effects (; ).
4 Applications of NPs in liver diseases
The accumulation characteristics of NPs within the liver and their interactions with various hepatic cells have been extensively studied, highlighting the potential applications of NPs in liver diseases. Given that each liver disease has a distinct pathogenesis, the design and targeting strategies for NPs vary significantly across different liver disorders. This section will summarize the pathological mechanisms of common liver diseases and discuss the applications of NPs in these conditions (Table 2). Figure 4 illustrates the diverse applications of NPs across various liver diseases and liver cell types.
TABLE 2
| Diseases | Targeted cells | Targeting approaches | Vector | Administration route | Animal model | Efficiency | References |
|---|---|---|---|---|---|---|---|
| ALF | Macrophages | Scavenger receptor-A | Palmitic acid-modified serum albumin | Intravenous | Mice | More than 50% NPs are taken up in liver, and the control group has almost no NPs uptake | Zhang et al. (2023a) |
| ALF | Hepatocyte | Antioxidant nanozyme-hepatocyte-like cells | N-acetylcysteine-capped gold nanoclusters, forming the N–Au@hydrogel | Intraperitoneal | Mice | The HS/N–Au@composite group also demonstrated the most favorable reductions in AST and ALT serum levels, effectively suppressing by 12.32-fold and 10.20-fold, respectively, compared to the control model group | |
| ALF | Hepatocyte | Conjugating acid-cleavable hydrophobic moieties to maltodextrin | Ketalized maltodextrin | Intravenous | Mice | A majority (∼70%) of drug payloads was released at 24 h | |
| ALF | Macrophages | Red blood cell membrane | Mesenchymal stem cells inspired biomimetic nanoframework | Intravenous | Mice | The final biomimetic nanostructure had a loading capacity of 6.98% for rhein and 7.51% for freezedried MSC-conditioned medium | |
| ALF | Porous silicon, gold NPs | Intravenous | Mice | More than 50% DPSi/DAu@AcDEX are taken up in liver, and the control group has almost no NPs uptake | |||
| ALF | Hepatocyte | Bovine serum albumin | Bilirubin and 18β-Glycyrrhetinic acid | Intravenous | Mice | B/BG@N expressed abundant luciferase activity in hepatocytes, while the control group has almost no luciferase uptake | Yao et al. (2023) |
| ALF | Macrophages | Macrophage membrane | PLGA NPs | Intravenous | Mice | MVs-DiD-NPs were observed with the highest fluorescence intensity in liver tissue | |
| ALF | Macrophages | Manganese porphyrin via π-π stacking interaction with G-quadruplex | DNA nanoplatform | Intravenous | Mice | TDN-siTNF-α/-G4-MnP4 shows almost complete liver accumulation after within 2 h | Wei et al. (2024a) |
| ALF | Macrophages | Phenylboronic acids | PEGylated, phenylboronic-acid-protected L-DOPA precursor NPs | Intravenous | Mice | PADN treatment displayed obvious efficacy in reducing AST levels over control group | Zhao et al. (2021) |
| NAFLD | Hepatocyte | Rubicon‐specific CRISPR‐Cas9 components | Lipid NPs | Intravenous | Mice | ≈90% of the NPs accumulated in the liver, while only ≈5% were detected in the spleen | |
| NAFLD | Hepatic stellate cells | CD44-targeting glycosaminoglycan biopolymer | Hyaluronic acid-bilirubin NPs | Intravenous | Mice | Higher fluorescence signals from HABN–Cy5.5 were found in the liver of mice kept on a CD-HFD than in their other organs | |
| NAFLD | Hepatocyte | Albumin | Natural compound ginsenoside compound K | Intravenous | Mice | NabCK supplementation increased fecal cholesterol and cholestanone by 2.86 and 56.32 times, respectively | Yue et al. (2023) |
| NAFLD | Hepatic stellate cells | Vitamin A | Aminoethyl anisamide coated in NPs | Intravenous | Mice | siRNA@Cy5.5NP-AEAA5% exhibited greater accumulation in fibrotic livers compared with nontargeted siRNA@Cy5.5NP | Zhang et al. (2023b) |
| NAFLD | TiO2, Au, and NaYF4 NPs | Oral administrations | Mice | Relative Ces2h mRNA expression of db/db mice increased by ∼2.9–3.3 times, depending on the types of NPs | |||
| NAFLD | Hepatocyte | Fluorineted polyesters | Biodegradable acid-activated acidifying NPs | Intravenous | Mice | Rhodamine-labeled PEFSU acNPs are rapidly taken up in HepG2 cells with 80% of the HepG2 cells possessing Rho-acNPs within 4 h | Zeng et al. (2023) |
| NAFLD | Macrophages | Prohibitin binding peptide | Hemin‐ or CoPP‐loaded poly NPs | Intravenous | Mice | PBP‐NPs were highly distributed in the fatty liver of the NASH model than what was observed in the liver of the T2DM model | |
| Liver fibrosis | Hepatic stellate cells | IL-11 scFv | Lipid NPs | Intravenous | Mice | Cy5AA3G LNP exhibited a higher and more specific distribution in the liver compared to the nontargeted Cy5AA3 LNP. | Zhang et al. (2024d) |
| Liver fibrosis | Hepatic stellate cells | Platelet membranes and hepatic stellate cell membranes | Poly (lactic-co-glycolic acid) @Melatonin | Intravenous | Mice | The fluorescence intensity observed with HSCM@PLGA@Cy7.5 was significantly higher than that of PLGA@Cy7.5, at all-time points | |
| Liver fibrosis | Liver sinusoidal endothelial cells and hepatic stellate cells | Chondroitin sulfate | Vismodegib-loaded NPs | Intravenous | Mice | Targeting ability of chondroitin sulfate and vismodegib to the highly expressed receptors in liver | Zhang et al. (2024e) |
| Liver fibrosis | Hepatic stellate cells | Ligands targeting M6P/IGF-II receptors | Dibenzocyclooctyne functionalised crosslinked micelles | Intravenous | Mice | The mannose-conjugated micelles and retinol-conjugated micelles exhibited consistent trends between in vitro and in vivo experiments | |
| Liver fibrosis | Macrophages | Ligands targeting RNF41 | Dendrimer-graphite NPs | Intravenous | Mice | An intense fluorescence signal in CD11b+ macrophages corresponding to the plasmid EGFP reporter | |
| Liver fibrosis | Self-assembling antagonist peptides NPs | Intravenous | Mice | The fluorescence of the DiR-F-NPs was mainly concentrated on the liver sites | |||
| Liver fibrosis | Hepatic stellate cells | CREKA (a specific ligand of fibronectin) and chondroitin sulfate (CS, a major ligand of CD44) | Lipid NPs | Intravenous | Mice | CCR NPs showed the highest fluorescent signal in CCl4-induced liver | |
| Liver fibrosis | Hepatic stellate cells | Bilirubinn | PEGylated NPs | Intravenous | Mice | Cy5.5@GBRNP fluorescence in the liver was 1.8-fold greater than that in the free Cy5.5 group and 1.5-fold compared to the Cy5.5@BRNP group | |
| HCC | Decoy receptor 3 antibodies | PEGylated paramagnetic NPs | Intravenous | Mice | Following coupling with the DCR3 antibody, the Fe NPs-DCR3 group exhibited more effective enrichment at liver tumor sites compared to the Fe NPs group | ||
| HCC | Heaptocellular carcinoma cells | FIDAS-5, macrophage membrane, and anti-PD-L1 | Hollow mesoporous manganese dioxide (MnO2) NPs | Intravenous | Mice | After treatment with MF, MFM, and MFMP, relatively high fluorescence was observed in the liver while pronounced fluorescence was only detected in the tumors of the MFMP groups | Zhu et al. (2024) |
| HCC | Heaptocellular carcinoma cells | Calcium-based thermosensitizer | CaCO3 NPs | Intravenous | Mice | Compared with the mice in the PBS group and the IR780 group alone, DMXAA@CBTNps arriving at the tumor site at 24 h still retained more NPs located in the tumor | Zeng et al. (2025) |
| HCC | Heaptocellular carcinoma cells | Ultrasound-magnified multienzyme-mimicking properties | Ultrasmall Bi2Sn2O7 nanozyme NPs | Intratumoral and Intravenous injection | Mice | Control group and BSO group maintained normal cell tissue morphology, whereas both intravenous and intratumoral injection of BSO + US group resulted in evident histopathological damage | Wei et al. (2024b) |
| HCC | Heaptocellular carcinoma cells | Man-DSPE-mPEG2K modified with mannose | DOTAP, DOPE, Cho, DSPE-mPEG2K, and HMME form liposomes | Intravenous | Mice | The maximum accumulation level in the MLipCy5-siBcl-2 group was significantly higher than that in the LipCy5-siBcl-2 group, indicating good in vivo targeting of MLipCy5-siBcl-2 | Wang et al. (2024c) |
| HCC | CD8+ T cells | PD1 proteins | Calcium phosphate NPs | Intravenous | Mice | siPDL1‐CaP@PD1‐NVs exhibited significantly higher fluorescent intensity in tumor than that of siPDL1‐CaP@NVs without PD1‐expressing on the cell membrane, indicating an efficient tumor targeting ability of siPDL1‐CaP@PD1‐NVs | |
| HCC | Heaptocellular carcinoma cells | Cationic poly (l-lysine) complexing anti-MFAP-5 siRNA | Polypept(o)ide-based polyion complex micelles | Intravenous | Mice | At 24 h post-administration, Cy5.5 signal from siCy5.5 PICMs and siCy5.5/DES PICMs was mainly located in the liver region, while the signal of siCy5.5-loaded in LNPs began to fade and was less localized in the liver region |
Applications of NPs to treat different liver diseases.
FIGURE 4
4.1 Applications of NPs in acute ALF
ALF is a critical condition characterized by the sudden and severe impairment of liver function in individuals with no pre-existing liver disease. The hallmark features of ALF include coagulopathy and hepatic encephalopathy, with extensive hepatocellular necrosis observed histologically. The pathogenesis of ALF involves extensive hepatocyte death, leading to the rapid decline in liver function. Viral infections, such as those caused by hepatitis B and C viruses, can trigger an immune response that results in hepatic inflammation and necrosis. Drug-induced liver injury occurs when certain medications or toxins directly damage hepatocytes or induce an immune-mediated reaction. Autoimmune hepatitis involves the body’s immune system attacking liver cells, causing chronic inflammation and acute deterioration. Currently, liver transplantation remains the most effective treatment for ALF; however, the scarcity of donor organs presents a significant challenge. Although artificial liver support systems can mitigate the progression of ALF to some extent, the mortality rate remains high.
NPs offer promising platforms for targeted therapy in ALF, especially in controlling the expressive inflammation in macrophages and promoting the regeneration of hepatocytes. For ALF, rapid intervention is critical, and nucleic acid-based nanoparticles, gold nanoparticles, and Lipid Nanoparticles have been most prevalent due to their excellent efficacy in gene silencing, anti-oxidative stress, and rapid hepatocyte uptake (Figure 4). One notable study involved the synthesis of SchB-PSA NPs, which were created by modifying palmitic acid-modified serum albumin with scavenger receptor-A (SR-A). These SchB-PSA NPs exhibited significant therapeutic potential by inhibiting the NF-κB pathway in macrophages and reducing hepatocyte necrosis, thereby lowering mortality rates in ALF mouse models (Zhang R. et al., 2023). Another innovative approach involves the use of gold NPs (AuNPs) within a 3D-printed hydrogel scaffold, encapsulating NAC-modified AuNPs to form HS/N–Au@composite. This composite targets necrotic areas in the liver, clears reactive oxygen species (ROS) within macrophages, and promotes the differentiation of macrophages from the M1 subtype to the M2 subtype, offering a novel strategy for ALF treatment (Figure 5) (). Furthermore, ketalized maltodextrin (KMD) NPs leverage pH-sensitive properties to release therapeutic drugs in the acidic regions of necrotic hepatocytes. This targeted delivery mechanism enhances ultrasound imaging capabilities and provides an effective means for targeting ALF treatment (). These studies collectively highlight the versatility and efficacy of NPs in addressing the complex pathologies associated with ALF.
FIGURE 5
4.2 Applications of NPs in NAFLD
As lifestyle changes contribute to the global rise of obesity and type 2 diabetes, the prevalence of NAFLD is significantly increasing. NAFLD often presents with subtle symptoms but can progress histologically to non-alcoholic steatohepatitis (NASH), which may further develop into advanced liver disease, cirrhosis, and hepatocellular carcinoma (Younossi, 2019). Statistics indicate that the global incidence of NAFLD is approximately 24% (). Predictably, as viral hepatitis is effectively controlled, NAFLD will impose a substantial health burden and economic cost (). Lifestyle modification remains the most effective and fundamental approach to treating NAFLD, yet it is challenging to implement (). Given the rapid global increase in NAFLD and NASH, developing early treatment strategies for these conditions is of paramount importance.
Macrophages play a crucial role in the development of NAFLD, making them a primary target for NPs-based therapies (). In the context of NAFLD, which often requires long-term management, polymeric NPs, silica nanoparticles, and exosomes have shown great promise for their sustained drug release profiles, high biocompatibility, and ability to modulate chronic inflammatory pathways (Figure 4). Given the chronic nature and long-term treatment requirements of NAFLD, oral administration is considered the most effective route for delivering NPs (). Studies comparing the hepatic uptake efficiency of orally administered TiO2, Au, and NaYF4 have demonstrated that these common NPs can effectively enter the liver. Further pathological analyses suggest that these NPs can reduce lipid accumulation and steatosis in hepatocytes, indicating promising applications for NPs in NAFLD treatment (Figure 6) (). Previous research has implicated Rubicon in the progression of NAFLD, suggesting that targeting this pathway could be beneficial (). Consequently, encapsulating CRISPR-Cas9 components targeting Rubicon within NPs has emerged as a potential therapeutic strategy. Results indicate that a single injection of NPs targeting Rubicon can enhance lipid metabolism in hepatocytes and alleviate NAFLD (). Traditional Chinese medicine has shown significant advantages in treating chronic diseases. Researchers have developed sustained-release NPs composed of ginsenoside compound K (CK) and albumin, known as nabCK. Animal models suggest that nabCK can promote lipid homeostasis in hepatocytes by reducing mTOR activation (Yue et al., 2023).
FIGURE 6
4.3 Applications of NPs in liver fibrosis
Liver cirrhosis is a stage in the progression of liver fibrosis. Clinically, cirrhosis is classified into compensated and decompensated phases. Once patients enter the decompensated phase, they exhibit symptoms of liver failure and portal hypertension, significantly impacting their quality of life (). Over the past few decades, viral hepatitis-induced cirrhosis has been somewhat controlled etiologically. However, once cirrhosis develops, it remains an irreversible progression towards liver failure or HCC (). Mechanistically, cirrhosis primarily results from inflammation promoting the activation of hepatic stellate cells, driving the deposition of extracellular matrix into fibrotic tissue. Therefore, inhibiting macrophage inflammation, reducing the recruitment of bone marrow mononuclear cells, or controlling the activation of stellate cells could potentially mitigate liver fibrosis ().
For Liver Fibrosis, silver nanoparticles for their anti-inflammatory properties, nucleic acid-based NPs for gene therapy, and Lipid Nanoparticles have been the most widely investigated (Figure 4). Fibrotic livers exhibit elevated expression of IL-11 (Zhang C. et al., 2023). Studies have developed antibodies targeting IL-11 and encapsulated their mRNA within AA3G NPs (mIL11-scFv@AA3G). In vivo imaging in mice demonstrated the high accumulation of mIL11-scFv@AA3G in the liver. Pathological results indicated a significant reduction in fibrosis levels in mice treated with mIL11-scFv@AA3G (Zhang C. et al., 2024). Oxidative stress damage to hepatocytes is also a crucial factor in fibrosis progression (). Researchers loaded melatonin into poly (lactic-co-glycolic acid) (PLGA) and coated it with platelet membranes (PM) and activated hepatic stellate cell membranes (HSCM), creating PM@PLGA@Melatonin and HSCM@PLGA@Melatonin, respectively. Experimental results showed that PM@PLGA@Melatonin and HSCM@PLGA@Melatonin could alleviate oxidative stress and endoplasmic reticulum stress in hepatic stellate cells, thereby reducing fibrosis levels (). Another study aimed to break the vicious cycle of liver fibrosis formation. The authors constructed chondroitin sulfate-modified and vismodegib-loaded NPs (CS NPs/VDG) to restore HSC homeostasis. Additionally, they prepared glycyrrhetinic acid-modified and silybin-loaded NPs (GA NPs/SIB) to mitigate oxidative stress in hepatocytes. The combined application of these two types of NPs was successfully practiced in a mouse model of liver fibrosis (Figure 7) (Zhang et al., 2024e).
FIGURE 7
4.4 Applications of NPs in HCC
Hepatic tumors represent the final stage of various liver diseases, with HCC being the most common primary liver malignancy (). HCC exhibits significant heterogeneity at both cellular and molecular levels. Currently, surgical resection and radiofrequency ablation are viable treatment options for early-stage HCC. For advanced HCC, chemotherapy and immunotherapy are employed (). However, due to the immune-privileged nature of the liver, many chemotherapeutic agents fail to reach the tumor site effectively, severely impacting treatment efficacy and increasing side effects (; ). This scenario presents a unique opportunity for targeted NPs therapies. NPs offer promising tools for overcoming the challenges associated with liver immunoprivilege and enhancing the delivery of therapeutic agents to the tumor site (). By leveraging their unique properties for targeted delivery and imaging, NPs can provide promising treatment strategies.
For HCC, the need for both therapy and imaging has made multifunctional platforms like silver nanoparticles (theranostics), silica nanoparticles (drug delivery), and polymeric NPs (versatile functionalization) the most extensively applied strategies (Figure 4). Recent advances have led to the development of a dual-responsive, magnetism-controlled drug delivery system based on PEGylated paramagnetic NPs coupled with decoy receptor 3 (DCR3). Upon entry into the body, these NPs move along DCR3 gradients to specifically target sites of HCC. They anchor at regions with the highest concentration of DCR3 and inhibit tumor progression (). Given that the function of immune cells such as CD8+ T cells is often suppressed in the tumor microenvironment (), leading to tumor proliferation and metastasis, another study combined GW4869 and amlodipine (AM) using polydopamine nanomodulators to synthesize NPs. This synergistic effect enhances the functionality of intratumoral CD8+ T cells and natural killer cells, effectively inhibiting tumor growth (Figure 8) (Zhu et al., 2024). Additionally, leveraging the local temperature differences within tumors (), researchers employed a calcium-based thermal-sensitive enhancer (CBT) for targeted therapy. The chemotherapeutic agent DMXAA was encapsulated within a CaCO3 shell and surface-modified with PEG to create DMXAA@CBTNps. Experimental results confirmed that DMXAA@CBTNps release drugs around the tumor, simultaneously increasing local temperature and releasing CO2, thereby achieving the goals of occluding tumor blood vessels and reducing tumor oxygen supply (Zeng et al., 2025).
FIGURE 8
5 Perspectives and conclusion
This review has elucidated the targeted strategies mediated by NPs and their applications in liver disease treatment. In contrast to the previous reviews of NPs technologies for liver targeting, the present review adopts a broader and more systematic approach. First, we provide a detailed synthesis of the liver’s unique anatomy and the principles governing the biological distribution of nanomaterials within it, serving as a foundational framework. Second, we extend the discussion beyond lipidic systems to include a side-by-side analysis of diverse nanomaterial classes, such as polymeric nanoparticles, metallic nanoparticles, and nucleic acid-based nanostructures, comparing their properties, applications, and targeting efficiencies. Finally, we systematically catalog their advanced applications across a spectrum of liver diseases, including ALF, NAFLD, liver fibrosis, and HCC, emphasizing the transformative potential of nanotechnology in advancing liver disease management.
The ability to tailor NP properties for enhanced hepatic uptake holds promise for improving the efficacy of treatments for liver diseases such as hepatitis, fibrosis, and cancer. However, several challenges must be addressed to fully harness the potential of NPs in this context. The size of NPs is a primary determinant of their biodistribution and cellular uptake. Development of precise synthesis methods that yield monodisperse NPs populations could enhance consistency and predictability of hepatic uptake (). Additionally, real-time monitoring techniques will aid in fine-tuning NPs size distributions for specific applications. Advanced fabrication techniques, such as those used in semiconductor manufacturing, could enable the production of well-defined shapes at the nanoscale (). Despite passive and active targeting strategies, achieving high enough specificity to diseased hepatic cells remains a significant challenge. Concerns regarding the biodegradation pathways, chronic toxicity, and eventual clearance of NPs and their components, especially for inorganic materials, need to be thoroughly addressed. Exploring shape-dependent effects systematically will provide deeper insights into optimizing hepatic delivery. Innovative surface modifications using zwitterionic polymers or hydrophilic coatings might balance between enhancing uptake and minimizing toxicity ().
Advancements in continuous flow reactors and automated synthesis platforms could improve scalability and reproducibility. Implementing rigorous quality control measures during production will ensure consistent performance across different batches (Zhang Q. et al., 2023). Furthermore, exploring biomimetic approaches where NP surfaces mimic natural ligands can improve specificity and reduce off-target effects. Developing more sophisticated in vitro liver models, such as organoids or microfluidic devices, could bridge the gap between simple cell cultures and whole organisms (). These models would allow for high-throughput screening and better prediction of clinical outcomes.
Another significant challenge is the biocompatibility and long-term toxicity of NPs. While many NP formulations have shown efficacy in pre-clinical models, concerns persist regarding their potential to induce immune responses or accumulate in off-target organs over time (). Development of novel ligands with higher affinity and specificity for markers uniquely overexpressed in specific liver diseases and cell types. Future studies must prioritize rigorous safety assessments to ensure that NPs can be used safely in clinical settings.
Looking ahead, the integration of multifunctional NPs that combine targeting ligands, therapeutic agents, and imaging probes holds great promise for theranostic applications. Such systems could enable real-time monitoring of treatment response and facilitate adaptive therapies tailored to evolving disease states. Additionally, exploring novel NP materials and surface coatings that enhance stability, reduce immunogenicity, and improve targeting specificity will be pivotal areas of research.
In conclusion, while NPs present a transformative opportunity in liver disease management, overcoming the aforementioned challenges through interdisciplinary collaboration and innovative research methodologies will be key to unlocking their full therapeutic potential and bringing them from bench to bedside.
Statements
Author contributions
MP: Data curation, Validation, Writing – original draft. FF: Validation, Writing – original draft. BW: Formal Analysis, Funding acquisition, Writing – review and editing.
Funding
The author(s) declare that financial support was received for the research and/or publication of this article. This study was supported by the National Natural Science Foundation of China (82501041) and Science and Technology Projects of Xizang Autonomous Region, China (ZRKX2024000383).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declare that no Generative AI was used in the creation of this manuscript.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Abbreviations
ALF, acute liver failure; AM, amlodipine; ApoE, apolipoprotein E; ASGPR, asialoglycoprotein receptor; AuNPs, gold nanoparticles; CBT, calcium-based thermal-sensitive enhancer; CK, ginsenoside compound K; DCR3, decoy receptor 3; EGFR-2, endothelial growth factor receptor-2; GalNAc, N-acetylgalactosamine; HCC, hepatocellular carcinoma; HER2, epidermal growth factor receptor-2; HSCM, hepatic stellate cell membranes; HSCs, hepatic stellate cells; IFN-γ, interferon-gamma; IL-2, interleukin-2; IL-4, interleukin-4; IL-10, interleukin-10; KCs, Kupffer cells; KMD, ketalized maltodextrin; LNP, Lipid-based NPs; LPS, lipopolyscharide; LSECs, sinusoidal endothelial cells; MPS, mononuclear phagocyte system; NAFLD, non-alcoholic fatty liver disease; NP, nanoparticles; PEG, polyethylene glycol; ROS, reactive oxygen species; SR-A, scavenger receptor-A.
References
1
Abdel-MisihS. R.BloomstonM. (2010). Liver anatomy. Surg. Clin. North Am.90 (4), 643–653. 10.1016/j.suc.2010.04.017
2
AdebayoD.NeongS. F.WongF. (2019). Refractory ascites in liver cirrhosis. Am. J. Gastroenterol.114 (1), 40–47. 10.1038/s41395-018-0185-6
3
ArjunanP.KathirveluD.MahalingamG.GoelA. K.ZacharaiahU. G.SrivastavaA.et al (2024). Lipid-nanoparticle-enabled nucleic acid therapeutics for liver disorders. Acta Pharm. Sin. B14 (7), 2885–2900. 10.1016/j.apsb.2024.04.015
4
BaiY.NanY.WuT.ZhuA.XieX.SunY.et al (2024a). Lipid nanoparticle-mediated delivery of CRISPR-Cas9 against rubicon ameliorates NAFLD by modulating CD36 along with glycerophospholipid metabolism. Adv. Sci. (Weinh)11 (31), e2400493. 10.1002/advs.202400493
5
BaiY.ChenJ.ZhangS.XuG.MaoZ.DingY.et al (2024b). Inflammation-responsive cell membrane-camouflaged nanoparticles against liver fibrosis via regulating endoplasmic reticulum stress and oxidative stress. Adv. Mater36 (19), e2310443. 10.1002/adma.202310443
6
BaiS.SunY.LiuM.ChengY.JiQ.ZhangB.et al (2025). Automatic target-seeking nanoparticle inhibiting orthotopic drug-resistant Colon cancer and liver metastases via regulating cancer cell adhesion and proliferation. J. Nanobiotechnology23 (1), 423. 10.1186/s12951-025-03422-x
7
BalajiA.BellC. A.HoustonZ. H.BridleK. R.GenzB.FletcherN. L.et al (2023). Exploring the impact of severity in hepatic fibrosis disease on the intrahepatic distribution of novel biodegradable nanoparticles targeted towards different disease biomarkers. Biomaterials302, 122318. 10.1016/j.biomaterials.2023.122318
8
BarrebyE.ChenP.AouadiM. (2022). Macrophage functional diversity in NAFLD - more than inflammation. Nat. Rev. Endocrinol.18 (8), 461–472. 10.1038/s41574-022-00675-6
9
BarrosA. S.PintoS.ViegasJ.MartinsC.AlmeidaH.AlvesI.et al (2024). Orally delivered stimulus-sensitive nanomedicine to harness teduglutide efficacy in inflammatory bowel disease. Small20 (45), e2402502. 10.1002/smll.202402502
10
BartneckM. (2021). Lipid nanoparticle formulations for targeting leukocytes with therapeutic RNA in liver fibrosis. Adv. Drug Deliv. Rev.173, 70–88. 10.1016/j.addr.2021.03.009
11
BitounisD.JacquinetE.RogersM. A.AmijiM. M. (2024). Strategies to reduce the risks of mRNA drug and vaccine toxicity. Nat. Rev. Drug Discov.23 (4), 281–300. 10.1038/s41573-023-00859-3
12
BoccaB.BattistiniB.PetrucciF. (2020). Silver and gold nanoparticles characterization by SP-ICP-MS and AF4-FFF-MALS-UV-ICP-MS in human samples used for biomonitoring. Talanta220, 121404. 10.1016/j.talanta.2020.121404
13
BoeyA.HoH. K. (2020). All roads lead to the liver: metal nanoparticles and their implications for liver health. Small16 (21), e2000153. 10.1002/smll.202000153
14
BottgerR.PauliG.ChaoP. H.Al FayezN.HohenwarterL.LiS. D. (2020). Lipid-based nanoparticle technologies for liver targeting. Adv. Drug Deliv. Rev.154-155, 79–101. 10.1016/j.addr.2020.06.017
15
BussinB.MacduffM.NgoW.WuJ. L. Y.LinZ. P.Granda FariasA.et al (2025). Discovering nanoparticle Corona ligands for liver macrophage capture. Nat. Nanotechnol.20 (7), 914–925. 10.1038/s41565-025-01903-6
16
CaiJ.PengJ.FengJ.LiR.RenP.ZangX.et al (2023). Antioxidant hepatic lipid metabolism can be promoted by orally administered inorganic nanoparticles. Nat. Commun.14 (1), 3643. 10.1038/s41467-023-39423-3
17
CaligiuriA.GentiliniA.PastoreM.GittoS.MarraF. (2021). Cellular and molecular mechanisms underlying liver fibrosis regression. Cells10 (10), 2759. 10.3390/cells10102759
18
CheZ.ZhouZ.LiS. Q.GaoL.XiaoJ.WongN. K. (2023). ROS/RNS as molecular signatures of chronic liver diseases. Trends Mol. Med.29 (11), 951–967. 10.1016/j.molmed.2023.08.001
19
ChenL.HeY.LanJ.LiZ.GuD.NieW.et al (2024a). Advancements in nano drug delivery system for liver cancer therapy based on mitochondria-targeting. Biomed. Pharmacother.180, 117520. 10.1016/j.biopha.2024.117520
20
ChenY.DaiS.ChengC. S.ChenL. (2024b). Lenvatinib and immune-checkpoint inhibitors in hepatocellular carcinoma: mechanistic insights, clinical efficacy, and future perspectives. J. Hematol. Oncol.17 (1), 130. 10.1186/s13045-024-01647-1
21
ChengQ.WeiT.FarbiakL.JohnsonL. T.DilliardS. A.SiegwartD. J. (2020). Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR-cas gene editing. Nat. Nanotechnol.15 (4), 313–320. 10.1038/s41565-020-0669-6
22
ChengZ.LiF.QieY.SunJ.WangY.ZhaoY.et al (2024). Hepatic stellate cell membrane-camouflaged nanoparticles for targeted delivery of an antifibrotic agent to hepatic stellate cells with enhanced antifibrosis efficacy. Nano Lett.24 (49), 15827–15836. 10.1021/acs.nanolett.4c04820
23
CostantiniP. E.SaporettiR.IencharelliM.FlamminiS.MontroneM.SanitàG.et al (2024). Phage-templated synthesis of targeted photoactive 1D-Thiophene nanoparticles. Small21, e2405832. 10.1002/smll.202405832
24
DasA.MukherjeeP.SinglaS. K.GuturuP.FrostM. C.MukhopadhyayD.et al (2010). Fabrication and characterization of an inorganic gold and silica nanoparticle mediated drug delivery system for nitric oxide. Nanotechnology21 (30), 305102. 10.1088/0957-4484/21/30/305102
25
DemirM.LangS.HartmannP.DuanY.MartinA.MiyamotoY.et al (2022). The fecal mycobiome in non-alcoholic fatty liver disease. J. Hepatol.76 (4), 788–799. 10.1016/j.jhep.2021.11.029
26
DoA.ZahrawiF.MehalW. Z. (2024). Therapeutic landscape of metabolic dysfunction-associated steatohepatitis (MASH). Nat. Rev. Drug Discov.24, 171–189. 10.1038/s41573-024-01084-2
27
Duran-LobatoM.Lopez-EstevezA. M.CordeiroA. S.DacobaT. G.Crecente-CampoJ.TorresD.et al (2021). Nanotechnologies for the delivery of biologicals: historical perspective and current landscape. Adv. Drug Deliv. Rev.176, 113899. 10.1016/j.addr.2021.113899
28
DykmanL.KhlebtsovB.KhlebtsovN. (2025). Drug delivery using gold nanoparticles. Adv. Drug Deliv. Rev.216, 115481. 10.1016/j.addr.2024.115481
29
EasaN.AlanyR. G.CarewM.VangalaA. (2019). A review of non-invasive insulin delivery systems for diabetes therapy in clinical trials over the past decade. Drug Discov. Today24 (2), 440–451. 10.1016/j.drudis.2018.11.010
30
ErgenC.HeymannF.AlR. W.GremseF.BartneckM.PanzerU.et al (2017). Targeting distinct myeloid cell populations in vivo using polymers, liposomes and microbubbles. Biomaterials114, 106–120. 10.1016/j.biomaterials.2016.11.009
31
FengD.GaoB. (2021). From basic liver immunology to therapeutic opportunities for liver diseases. Cell Mol. Immunol.18 (1), 1–3. 10.1038/s41423-020-00607-2
32
FengT.HuJ.WenJ.QianZ.CheG.ZhouQ.et al (2024a). Personalized nanovaccines for treating solid cancer metastases. J. Hematol. Oncol.17 (1), 115. 10.1186/s13045-024-01628-4
33
FengR.FanY.ZhangX.ChenL.ZhongZ. F.WangY.et al (2024b). A biomimetic multifunctional nanoframework for symptom relief and restorative treatment of acute liver failure. ACS Nano18 (7), 5951–5964. 10.1021/acsnano.4c00173
34
FengY.TaiW.HuangP.QiS.YuX.LiM.et al (2025). Albumin-recruiting lipid nanoparticle potentiates the safety and efficacy of mRNA vaccines by avoiding liver accumulation. Nat. Mater. 10.1038/s41563-025-02284-w
35
GageB. K.LiuJ. C.InnesB. T.MacParlandS. A.McGilvrayI. D.BaderG. D.et al (2020). Generation of functional liver sinusoidal endothelial cells from human pluripotent stem-cell-derived venous angioblasts. Cell Stem Cell27 (2), 254–269.e9. 10.1016/j.stem.2020.06.007
36
Gallego-DuranR.HadjihambiA.AmpueroJ.RoseC. F.JalanR.Romero-GómezM. (2024). Ammonia-induced stress response in liver disease progression and hepatic encephalopathy. Nat. Rev. Gastroenterol. Hepatol.21 (11), 774–791. 10.1038/s41575-024-00970-9
37
GaoB. (2016). Basic liver immunology. Cell Mol. Immunol.13 (3), 265–266. 10.1038/cmi.2016.09
38
GinesP.KragA.AbraldesJ. G.SolàE.FabrellasN.KamathP. S. (2021). Liver cirrhosis. Lancet398 (10308), 1359–1376. 10.1016/s0140-6736(21)01374-x
39
GoY.LeeH.JeongL.SunS.HongE.JungE.et al (2018). Acid-triggered echogenic nanoparticles for contrast-enhanced ultrasound imaging and therapy of acute liver failure. Biomaterials186, 22–30. 10.1016/j.biomaterials.2018.09.034
40
GovaereO.PetersenS. K.Martinez-LopezN.WoutersJ.Van HaeleM.MancinaR. M.et al (2022). Macrophage scavenger receptor 1 mediates lipid-induced inflammation in non-alcoholic fatty liver disease. J. Hepatol.76 (5), 1001–1012. 10.1016/j.jhep.2021.12.012
41
GreuterT.YaqoobU.GanC.Jalan-SakrikarN.KostallariE.LuJ.et al (2022). Mechanotransduction-induced glycolysis epigenetically regulates a CXCL1-dominant angiocrine signaling program in liver sinusoidal endothelial cells in vitro and in vivo. J. Hepatol.77 (3), 723–734. 10.1016/j.jhep.2022.03.029
42
GuoC.GaoF.WuG.LiJ.ShengC.HeS.et al (2024). Precise HER2 protein degradation via peptide-conjugated photodynamic therapy for enhanced breast cancer immunotherapy. Adv. Sci. (Weinh)12, e2410778. 10.1002/advs.202410778
43
HammouteneA.RautouP. E. (2019). Role of liver sinusoidal endothelial cells in non-alcoholic fatty liver disease. J. Hepatol.70 (6), 1278–1291. 10.1016/j.jhep.2019.02.012
44
HaoN.PeiZ.LiuP.BachmanH.NaquinT. D.ZhangP.et al (2020). Acoustofluidics-assisted Fluorescence-SERS bimodal biosensors. Small16 (48), e2005179. 10.1002/smll.202005179
45
HeQ.ZhangJ.ChenF.GuoL.ZhuZ.ShiJ. (2010). An anti-ROS/hepatic fibrosis drug delivery system based on salvianolic acid B loaded mesoporous silica nanoparticles. Biomaterials31 (30), 7785–7796. 10.1016/j.biomaterials.2010.07.008
46
HeX.ChangZ.ChenF.ZhangW.SunM.ShiT.et al (2024a). Engineering a biomimetic system for hepatocyte-specific RNAi treatment of non-alcoholic fatty liver disease. Acta Biomater.174, 281–296. 10.1016/j.actbio.2023.10.038
47
HeY.PengE.BaX.WuJ.DengW.HuangQ.et al (2024b). ROS responsive cerium oxide biomimetic nanoparticles alleviates calcium oxalate crystals induced kidney injury via suppressing oxidative stress and M1 macrophage polarization. Small21, e2405417. 10.1002/smll.202405417
48
HongJ.KimY. H. (2022). Fatty liver/adipose tissue dual-targeting nanoparticles with heme Oxygenase-1 inducer for amelioration of obesity, obesity-induced type 2 diabetes, and steatohepatitis. Adv. Sci. (Weinh)9 (33), e2203286. 10.1002/advs.202203286
49
HornP.TackeF. (2024). Metabolic reprogramming in liver fibrosis. Cell Metab.36 (7), 1439–1455. 10.1016/j.cmet.2024.05.003
50
HouY.ConklinB.ChoiH. K.YangL.LeeK. B. (2024). Probing nanotopography-mediated macrophage polarization via integrated machine learning and combinatorial biophysical cue mapping. ACS Nano18 (37), 25465–25477. 10.1021/acsnano.4c04406
51
HuY.NieW.LyuL.ZhangX.WangW.ZhangY.et al (2024a). Tumor-microenvironment-Activatable nanoparticle mediating immunogene therapy and M2 macrophage-targeted inhibitor for synergistic cancer immunotherapy. ACS Nano18 (4), 3295–3312. 10.1021/acsnano.3c10037
52
HuG.LiuQ.DengH. (2024b). Space exploration of metal-organic frameworks in the Mesopore regime. Acc. Chem. Res.58, 73–86. 10.1021/acs.accounts.4c00633
53
HuangD. Q.El-SeragH. B.LoombaR. (2021). Global epidemiology of NAFLD-Related HCC: trends, predictions, risk factors and prevention. Nat. Rev. Gastroenterol. Hepatol.18 (4), 223–238. 10.1038/s41575-020-00381-6
54
HulugallaK.Shofolawe-BakareO.ToragallV. B.MohammadS. A.MayattR.HandK.et al (2024). Glycopolymeric nanoparticles enrich less immunogenic protein coronas, reduce mononuclear phagocyte clearance, and improve tumor delivery compared to PEGylated nanoparticles. ACS Nano18 (44), 30540–30560. 10.1021/acsnano.4c08922
55
JainH.KumarA.AlmousaS.MishraS.LangstenK. L.KimS.et al (2024). Characterisation of LPS+ bacterial extracellular vesicles along the gut-hepatic portal vein-liver axis. J. Extracell. Vesicles13 (7), e12474. 10.1002/jev2.12474
56
JiaL.DaiY.XuY.SunH.GaoH.HaoH.et al (2024). Dual responsive magnetic DCR3 nanoparticles: a new strategy for efficiently targeting hepatocellular carcinoma. Small21, e2402909. 10.1002/smll.202402909
57
JinY.ZhangJ.ChenX.LiF.XueT.YiK.et al (2025). 3D printing incorporating gold nanozymes with mesenchymal stem cell-derived hepatic spheroids for acute liver failure treatment. Biomaterials315, 122895. 10.1016/j.biomaterials.2024.122895
58
KanZ.MadoffD. C. (2008). Liver anatomy: microcirculation of the liver. Semin. Interv. Radiol.25 (2), 077–085. 10.1055/s-2008-1076685
59
KentS. J.LiS.AmarasenaT. H.ReynaldiA.LeeW. S.LeemingM. G.et al (2024). Blood distribution of SARS-CoV-2 lipid nanoparticle mRNA vaccine in humans. ACS Nano18 (39), 27077–27089. 10.1021/acsnano.4c11652
60
KimM.JeongM.HurS.ChoY.ParkJ.JungH.et al (2021). Engineered ionizable lipid nanoparticles for targeted delivery of RNA therapeutics into different types of cells in the liver. Sci. Adv.7 (9), eabf4398. 10.1126/sciadv.abf4398
61
KimK. R.KimJ.BackJ. H.LeeJ. E.AhnD. R. (2022). Cholesterol-mediated seeding of protein Corona on DNA nanostructures for targeted delivery of oligonucleotide therapeutics to treat liver fibrosis. ACS Nano16 (5), 7331–7343. 10.1021/acsnano.1c08508
62
KisselevaT.BrennerD. (2021). Molecular and cellular mechanisms of liver fibrosis and its regression. Nat. Rev. Gastroenterol. Hepatol.18 (3), 151–166. 10.1038/s41575-020-00372-7
63
KoJ.KimJ.KiK.MoonS.JeonH.ParkJ. H.et al (2024). Shape-dependent locomotion of DNA-linked magnetic nanoparticle films. Nano Lett.25, 419–425. 10.1021/acs.nanolett.4c05189
64
KrischerJ. P.SchatzD. A.BundyB.SkylerJ. S.GreenbaumC. J. (2017). Effect of oral insulin on prevention of diabetes in relatives of patients with type 1 diabetes: a randomized clinical trial. JAMA318 (19), 1891–1902. 10.1001/jama.2017.17070
65
KrishnanG.SubramaniyanJ.ChengalvarayanS. P.MuralidharanB.ThiruvengadamD. (2017). Hesperetin conjugated PEGylated gold nanoparticles exploring the potential role in anti-inflammation and anti-proliferation during diethylnitrosamine-induced hepatocarcinogenesis in rats. Asian J. Pharm. Sci.12 (5), 442–455. 10.1016/j.ajps.2017.04.001
66
KulcharR. J.SinghR.DingS.AlexanderE.LeongK. W.DaniellH. (2023). Delivery of biologics: topical administration. Biomaterials302, 122312. 10.1016/j.biomaterials.2023.122312
67
LaiM.AfdhalN. H. (2019). Liver fibrosis determination. Gastroenterol. Clin. North Am.48 (2), 281–289. 10.1016/j.gtc.2019.02.002
68
LanZ.ChenR.ZouD.ZhaoC. (2024). Microfluidic nanoparticle separation for precision medicine. Adv. Sci. (Weinh)12, e2411278. 10.1002/advs.202411278
69
LankveldD. P.OomenA. G.KrystekP.NeighA.Troost – de JongA.NoorlanderC.et al (2010). The kinetics of the tissue distribution of silver nanoparticles of different sizes. Biomaterials31 (32), 8350–8361. 10.1016/j.biomaterials.2010.07.045
70
LeberN.KapsL.AslamM.SchuppJ.BroseA.SchäffelD.et al (2017). SiRNA-mediated in vivo gene knockdown by acid-degradable cationic nanohydrogel particles. J. Control Release248, 10–23. 10.1016/j.jconrel.2016.12.006
71
LiQ.DingY.GuoX.LuoS.ZhuangH.ZhouJ.et al (2019). Chemically modified liposomes carrying TRAIL target activated hepatic stellate cells and ameliorate hepatic fibrosis in vitro and in vivo. J. Cell Mol. Med.23 (3), 1951–1962. 10.1111/jcmm.14097
72
LiB.HuangY.BaoJ.XuZ.YanX.ZouQ. (2023a). Supramolecular nanoarchitectonics based on antagonist peptide self-assembly for treatment of liver fibrosis. Small19 (45), e2304675. 10.1002/smll.202304675
73
LiY.ZhangT.ZhangJ.LiuQ.JiaQ.ChenW.et al (2023b). Dually fibronectin/CD44-mediated nanoparticles targeted disrupt the golgi apparatus and inhibit the hedgehog signaling in activated hepatic stellate cells to alleviate liver fibrosis. Biomaterials301, 122232. 10.1016/j.biomaterials.2023.122232
74
LiF.ChengZ.SunJ.ChengX.LiC.WuZ.et al (2023c). The combination of sinusoidal perfusion enhancement and apoptosis inhibition by riociguat plus a Galactose-PEGylated bilirubin multiplexing nanomedicine ameliorates liver fibrosis progression. Nano Lett.23 (10), 4126–4135. 10.1021/acs.nanolett.2c04726
75
LiS.Cortez-JugoC.JuY.CarusoF. (2024a). Approaching two decades: biomolecular coronas and bio-nano interactions. ACS Nano18 (49), 33257–33263. 10.1021/acsnano.4c13214
76
LiX.GaoM. L.WangS. S.HuY.HouD.LiuP. N.et al (2024b). Nanoscale covalent organic framework-mediated pyroelectrocatalytic activation of immunogenic cell death for potent immunotherapy. Sci. Adv.10 (48), r5145. 10.1126/sciadv.adr5145
77
LiH.HuY.ZhangY.ZhangH.YaoD.LinY.et al (2024c). Metal halide perovskite nanocrystals-intermediated hydrogel for boosting the biosensing performance. Adv. Mater36 (46), e2409090. 10.1002/adma.202409090
78
LiH.OuyangY.LvH.LiangH.LuoS.ZhangY.et al (2025). Nanoparticle-mediated klotho gene therapy prevents acute kidney injury to chronic kidney disease transition through regulating PPARα signaling in renal tubular epithelial cells. Biomaterials315, 122926. 10.1016/j.biomaterials.2024.122926
79
LinT.GaoD. Y.LiuY. C.SungY. C.WanD.LiuJ. Y.et al (2016). Development and characterization of sorafenib-loaded PLGA nanoparticles for the systemic treatment of liver fibrosis. J. Control Release221, 62–70. 10.1016/j.jconrel.2015.11.003
80
LinJ.YuZ.GaoX. (2024). Advanced noninvasive strategies for the brain delivery of therapeutic proteins and peptides. ACS Nano18 (34), 22752–22779. 10.1021/acsnano.4c06851
81
LiuZ.LiY.LiW.XiaoC.LiuD.DongC.et al (2018). Multifunctional nanohybrid based on porous silicon nanoparticles, gold nanoparticles, and acetalated dextran for liver regeneration and acute liver failure theranostics. Adv. Mater30 (24), e1703393. 10.1002/adma.201703393
82
LiuJ.LiuJ.MuW.MaQ.ZhaiX.JinB.et al (2024). Delivery strategy to enhance the therapeutic efficacy of liver fibrosis via nanoparticle drug delivery systems. ACS Nano18 (32), 20861–20885. 10.1021/acsnano.4c02380
83
LlovetJ. M.KelleyR. K.VillanuevaA.SingalA. G.PikarskyE.RoayaieS.et al (2021). Hepatocellular carcinoma. Nat. Rev. Dis. Prim.7 (1), 6. 10.1038/s41572-020-00240-3
84
LlovetJ. M.CastetF.HeikenwalderM.MainiM. K.MazzaferroV.PinatoD. J.et al (2022). Immunotherapies for hepatocellular carcinoma. Nat. Rev. Clin. Oncol.19 (3), 151–172. 10.1038/s41571-021-00573-2
85
Lozano-SanchezE.DarosJ. A.MerwaissF. (2024). Production of plant virus-derived hybrid nanoparticles decorated with different nanobodies. ACS Nano18 (50), 33890–33906. 10.1021/acsnano.4c07066
86
LuH.RenY.QiY.XuM.LiangF.WangZ.et al (2024). Overcoming hepatic biotransformation barrier of gold nanoparticles via Au-Se bond for enhanced in vivo active targeting. ACS Nano18 (42), 29178–29188. 10.1021/acsnano.4c10700
87
LyuY.YangX.YangL.DaiJ.QinH.ZhouY.et al (2024). Lipid nanoparticle-mediated hepatocyte delivery of siRNA and silibinin in metabolic dysfunction-associated steatotic liver disease. J. Control Release373, 385–398. 10.1016/j.jconrel.2024.07.011
88
MaW.YangY.ZhuJ.JiaW.ZhangT.LiuZ.et al (2022). Biomimetic Nanoerythrosome-Coated Aptamer-DNA tetrahedron/maytansine conjugates: ph-responsive and targeted cytotoxicity for HER2-Positive breast cancer. Adv. Mater34 (46), e2109609. 10.1002/adma.202109609
89
MalikU.HubeschR.KoleyP.MazurM.MehlaS.ButtiS. K.et al (2023). Surface functionalized 3D printed metal structures as next generation recyclable SERS substrates. Chem. Commun. (Camb)59 (90), 13406–13420. 10.1039/d3cc04154a
90
McconnellM. J.KostallariE.IbrahimS. H.IwakiriY. (2023). The evolving role of liver sinusoidal endothelial cells in liver health and disease. Hepatology78 (2), 649–669. 10.1097/hep.0000000000000207
91
MitchellM. J.BillingsleyM. M.HaleyR. M.WechslerM. E.PeppasN. A.LangerR. (2021). Engineering precision nanoparticles for drug delivery. Nat. Rev. Drug Discov.20 (2), 101–124. 10.1038/s41573-020-0090-8
92
MizutaR.KanaoE.UkyoK.KuwadaS.SawadaS. i.IshihamaY.et al (2024). A direct approach for living biomembrane printing on a nanoparticle. Nano Lett. 10.1021/acs.nanolett.4c03293
93
MoghimiS. M.McculloughR.SimbergD. (2023). Revisiting nanoparticle transendothelial migration in the liver. Mol. Ther.31 (3), 605–606. 10.1016/j.ymthe.2023.01.024
94
Moreno-LancetaA.Medrano-BoschM.FundoraY.PerramónM.AspasJ.Parra-RobertM.et al (2023). RNF41 orchestrates macrophage-driven fibrosis resolution and hepatic regeneration. Sci. Transl. Med.15 (704), q6225. 10.1126/scitranslmed.abq6225
95
MuX.HuangZ.FengW.ZhaiM.WangY.ZhouD.et al (2023). Zwitterionic rhodamine-CPT prodrug nanoparticles with GSH/H(2)O(2) responsiveness for cancer theranostics. Theranostics13 (1), 267–277. 10.7150/thno.78884
96
NgoW.AhmedS.BlackadarC.BussinB.JiQ.MladjenovicS. M.et al (2022). Why nanoparticles prefer liver macrophage cell uptake in vivo. Adv. Drug Deliv. Rev.185, 114238. 10.1016/j.addr.2022.114238
97
NiuX.MengY.CuiJ.LiR.DingX.NiuB.et al (2023). Hepatic stellate Cell- and liver microbiome-specific delivery system for dihydrotanshinone I to ameliorate liver fibrosis. ACS Nano17 (23), 23608–23625. 10.1021/acsnano.3c06626
98
PabstO.HornefM. W.SchaapF. G.CerovicV.ClavelT.BrunsT. (2023). Gut-liver axis: barriers and functional circuits. Nat. Rev. Gastroenterol. Hepatol.20 (7), 447–461. 10.1038/s41575-023-00771-6
99
PilkingtonE. H.SuysE.TrevaskisN. L.WheatleyA. K.ZukancicD.AlgarniA.et al (2021). From influenza to COVID-19: lipid nanoparticle mRNA vaccines at the frontiers of infectious diseases. Acta Biomater.131, 16–40. 10.1016/j.actbio.2021.06.023
100
PowellE. E.WongV. W.RinellaM. (2021). Non-alcoholic fatty liver disease. Lancet397 (10290), 2212–2224. 10.1016/s0140-6736(20)32511-3
101
Ramirez-VelezI.NamjoshiA. A.EffiongU. M.PeppasN. A.BelardiB. (2024). Paracellular delivery of protein drugs with smart EnteroPatho nanoparticles. ACS Nano18 (32), 21038–21051. 10.1021/acsnano.4c02116
102
RongA.HanZ.ZhouM.NieC.ZhuM.ChengS.et al (2024). Respiratory delivery of single low-dose nebulized PFCE-C25 NEs for lymphatic transport and durable stimulation of antitumor immunity in lung cancer. Sci. Adv.10 (48), p7561. 10.1126/sciadv.adp7561
103
SahaK.RahimiM.YazdaniM.KimS. T.MoyanoD. F.HouS.et al (2016). Regulation of macrophage recognition through the interplay of nanoparticle surface functionality and protein Corona. ACS Nano10 (4), 4421–4430. 10.1021/acsnano.6b00053
104
SayourE. J.BoczkowskiD.MitchellD. A.NairS. K. (2024). Cancer mRNA vaccines: clinical advances and future opportunities. Nat. Rev. Clin. Oncol.21 (7), 489–500. 10.1038/s41571-024-00902-1
105
SchneiderP.ZhangH.SimicL.DaiZ.SchrörsB.Akilli‐ÖztürkÖ.et al (2024). Multicompartment polyion complex micelles based on triblock polypept(o)ides mediate efficient siRNA delivery to cancer-associated fibroblasts for antistromal therapy of hepatocellular carcinoma. Adv. Mater36 (41), e2404784. 10.1002/adma.202404784
106
SchofieldR. M.MaciejewskaB. M.ElmestekawyK. A.WoolleyJ. M.TebbuttG. T.DanaieM.et al (2024). Nanostructure and photovoltaic potential of plasmonic nanofibrous active layers. Small21, e2409269. 10.1002/smll.202409269
107
SchottlerS.BeckerG.WinzenS.SteinbachT.MohrK.LandfesterK.et al (2016). Protein adsorption is required for stealth effect of poly(ethylene glycol)- and poly(phosphoester)-coated nanocarriers. Nat. Nanotechnol.11 (4), 372–377. 10.1038/nnano.2015.330
108
SeifalianA. M.StansbyG. P.HobbsK. E.HawkesD. J.ColchesterA. C. F. (1991). Measurement of liver blood flow: a review. HPB Surg.4 (3), 171–186. 10.1155/1991/68915
109
ShangJ.LiangT.WeiD.QinF.YangJ.YeY.et al (2023). Quercetin-loaded PLGA nanoparticles coating with macrophage membranes for targeted delivery in acute liver injury. Nanotechnology35 (11), 115102. 10.1088/1361-6528/ad1440
110
ShenT.SunX.YangS.WangW.ChenZ.LinY.et al (2024). Innovative oral nano/gene delivery system based on engineered modified Saccharomyces cerevisiae for colorectal cancer therapy. ACS Nano18 (41), 28212–28227. 10.1021/acsnano.4c08044
111
ShinnJ.ParkS.LeeS.ParkN.KimS.HwangS.et al (2024). Antioxidative hyaluronic acid-bilirubin nanomedicine targeting activated hepatic stellate cells for anti-hepatic-fibrosis therapy. ACS Nano18 (6), 4704–4716. 10.1021/acsnano.3c06107
112
StalderT.ZaiterT.El-BassetW.CornuR.MartinH.Diab-AssafM.et al (2022). Interaction and toxicity of ingested nanoparticles on the intestinal barrier. Toxicology481, 153353. 10.1016/j.tox.2022.153353
113
SunY.LiuY.LiR.ZhangC.WuM.ZhangX.et al (2024). Multifunctional biomimetic nanocarriers for dual-targeted immuno-gene therapy against hepatocellular carcinoma. Adv. Sci. (Weinh)11 (34), e2400951. 10.1002/advs.202400951
114
TanakaS.HikitaH.TatsumiT.SakamoriR.NozakiY.SakaneS.et al (2016). Rubicon inhibits autophagy and accelerates hepatocyte apoptosis and lipid accumulation in nonalcoholic fatty liver disease in mice. Hepatology64 (6), 1994–2014. 10.1002/hep.28820
115
TaoF.SalmeronM. (2024). Surface restructuring and predictive design of heterogeneous catalysts. Science386 (6724), eadq0102. 10.1126/science.adq0102
116
TargherG.MantovaniA.ByrneC. D.TilgH. (2024). Recent advances in incretin-based therapy for MASLD: from single to dual or triple incretin receptor agonists. Gut74, 487–497. 10.1136/gutjnl-2024-334023
117
TaruV.SzaboG.MehalW.ReibergerT. (2024). Inflammasomes in chronic liver disease: hepatic injury, fibrosis progression and systemic inflammation. J. Hepatol.81 (5), 895–910. 10.1016/j.jhep.2024.06.016
118
TengS.ZhengN.Al-HuqailA. A.LuY.AliE.AliH. E.et al (2023). Effect of nanoparticle macroalgae in the treatment of fatty liver disease using logistic regression, and support vector machine. Environ. Res.224, 115426. 10.1016/j.envres.2023.115426
119
TranahT. H.EdwardsL. A.SchnablB.ShawcrossD. L. (2021). Targeting the gut-liver-immune axis to treat cirrhosis. Gut70 (5), 982–994. 10.1136/gutjnl-2020-320786
120
TsoiK. M.MacparlandS. A.MaX. Z.SpetzlerV. N.EcheverriJ.OuyangB.et al (2016). Mechanism of hard-nanomaterial clearance by the liver. Nat. Mater15 (11), 1212–1221. 10.1038/nmat4718
121
Vivero-EscotoJ. L.VadarevuH.JunejaR.SchrumL. W.BenbowJ. H. (2019). Nanoparticle mediated silencing of tenascin C in hepatic stellate cells: effect on inflammatory gene expression and cell migration. J. Mater Chem. B7 (46), 7396–7405. 10.1039/c9tb01845j
122
VogelA.MeyerT.SapisochinG.SalemR.SaborowskiA. (2022). Hepatocellular carcinoma. Lancet400 (10360), 1345–1362. 10.1016/s0140-6736(22)01200-4
123
WalradtT.JirapinyoP. (2024). Endoscopic management of obesity and metabolic diseases. Trends Endocrinol. Metab.36, 373–385. 10.1016/j.tem.2024.11.001
124
WangM.ZhangM.FuL.LinJ.ZhouX.ZhouP.et al (2020). Liver-targeted delivery of TSG-6 by calcium phosphate nanoparticles for the management of liver fibrosis. Theranostics10 (1), 36–49. 10.7150/thno.37301
125
WangR.TangR.LiB.MaX.SchnablB.TilgH. (2021). Gut microbiome, liver immunology, and liver diseases. Cell Mol. Immunol.18 (1), 4–17. 10.1038/s41423-020-00592-6
126
WangD.JiangQ.DongZ.MengT.HuF.WangJ.et al (2023). Nanocarriers transport across the gastrointestinal barriers: the contribution to oral bioavailability via blood circulation and lymphatic pathway. Adv. Drug Deliv. Rev.203, 115130. 10.1016/j.addr.2023.115130
127
WangY.YaoY.ZhangY.YuY.LuoJ.SweetM. J.et al (2024a). Rational design of advanced gene delivery carriers: macrophage phenotype matters. Adv. Mater37, e2401504. 10.1002/adma.202401504
128
WangR.LiangQ.ZhangQ.ZhaoS.LinY.LiuB.et al (2024b). Ccl2-Induced regulatory T cells balance inflammation through macrophage polarization during liver reconstitution. Adv. Sci. (Weinh)11 (45), e2403849. 10.1002/advs.202403849
129
WangG.LuH.PanY.QiY.HuangY. (2024c). Ultrasound-sensitive targeted liposomes as a gene delivery system for the synergistic treatment of hepatocellular carcinoma. Small20 (47), e2406182. 10.1002/smll.202406182
130
WeiH.YiK.LiF.LiD.YangJ.ShiR.et al (2024a). Multimodal tetrahedral DNA nanoplatform for surprisingly rapid and significant treatment of acute liver failure. Adv. Mater36 (30), e2305826. 10.1002/adma.202305826
131
WeiW.WangH.RenC.DengR.QinQ.DingL.et al (2024b). Ultrasmall enzyodynamic PANoptosis nano-inducers for ultrasound-amplified hepatocellular carcinoma therapy and lung metastasis inhibition. Adv. Mater36 (45), e2409618. 10.1002/adma.202409618
132
WittenJ.RajiI.MananR. S.BeyerE.BartlettS.TangY.et al (2024). Artificial intelligence-guided design of lipid nanoparticles for pulmonary gene therapy. Nat. Biotechnol. 10.1038/s41587-024-02490-y
133
XuM.QiY.LiuG.SongY.JiangX.DuB. (2023). Size-dependent in vivo transport of nanoparticles: implications for delivery, targeting, and clearance. ACS Nano17 (21), 20825–20849. 10.1021/acsnano.3c05853
134
XuJ.YuY.ZhangY.DaiH.YangQ.WangB.et al (2024). Oral administration of garlic-derived nanoparticles improves cancer immunotherapy by inducing intestinal IFNγ-producing γδ T cells. Nat. Nanotechnol.19 (10), 1569–1578. 10.1038/s41565-024-01722-1
135
YanN.WangY.WongT. Y.WuZ.WangX.XieM.et al (2024). Spatiotemporal mapping of the evolution of silver nanoparticles in living cells. ACS Nano18, 35013–35028. 10.1021/acsnano.4c13880
136
YangL.HeR.ChaiJ.QiX.XueQ.BiX.et al (2024a). Synthesis strategies for high entropy nanoparticles. Adv. Mater37, e2412337. 10.1002/adma.202412337
137
YangM.WangR.XieY.ZhuL.HuangJ.XuW. (2024b). Applications of DNA functionalized gold nanozymes in biosensing. Biosens. Bioelectron.271, 116987. 10.1016/j.bios.2024.116987
138
YaoQ.TangY.DaiS.HuangL.JiangZ.ZhengS.et al (2023). A biomimetic nanoparticle exerting protection against acute liver failure by suppressing CYP2E1 activity and scavenging excessive ROS. Adv. Healthc. Mater12 (24), e2300571. 10.1002/adhm.202300571
139
YapK. K.GerrandY. W.DingleA. M.YeohG. C.MorrisonW. A.MitchellG. M. (2020). Liver sinusoidal endothelial cells promote the differentiation and survival of mouse vascularised hepatobiliary organoids. Biomaterials251, 120091. 10.1016/j.biomaterials.2020.120091
140
YazdiM.PohmererJ.HasanzadehK. M.SeidlJ.GrauM.HöhnM.et al (2024). In vivo endothelial cell gene silencing by siRNA-LNPs tuned with lipoamino bundle chemical and ligand targeting. Small20 (42), e2400643. 10.1002/smll.202400643
141
YeoY. H.AbdelmalekM.KhanS.MoylanC. A.RodriquezL.VillanuevaA.et al (2024). Current and emerging strategies for the prevention of hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol.22, 173–190. 10.1038/s41575-024-01021-z
142
YounossiZ. M. (2019). Non-alcoholic fatty liver disease - a global public health perspective. J. Hepatol.70 (3), 531–544. 10.1016/j.jhep.2018.10.033
143
YueC.LiD.FanS.TaoF.YuY.LuW.et al (2023). Long-term and liver-selected ginsenoside C-K nanoparticles retard NAFLD progression by restoring lipid homeostasis. Biomaterials301, 122291. 10.1016/j.biomaterials.2023.122291
144
ZaleskiM. H.ChaseL. S.HoodE. D.WangZ.NongJ.EspyC. L.et al (2024). Conjugation chemistry markedly impacts toxicity and biodistribution of targeted nanoparticles, mediated by complement activation. Adv. Mater37, e2409945. 10.1002/adma.202409945
145
ZelepukinI. V.ShevchenkoK. G.DeyevS. M. (2024). Rediscovery of mononuclear phagocyte system blockade for nanoparticle drug delivery. Nat. Commun.15 (1), 4366. 10.1038/s41467-024-48838-5
146
ZengJ.Acin-PerezR.AssaliE. A.MartinA.BrownsteinA. J.PetcherskiA.et al (2023). Restoration of lysosomal acidification rescues autophagy and metabolic dysfunction in non-alcoholic fatty liver disease. Nat. Commun.14 (1), 2573. 10.1038/s41467-023-38165-6
147
ZengG.LiangX.LingY.ZhuX.WangQ.LiZ.et al (2025). Tumor vascular occlusion by calcium-based thermosensitizer provokes continuous cavitation effect and thermal energy transition efficiency of radiofrequency ablation therapy. Biomaterials315, 122944. 10.1016/j.biomaterials.2024.122944
148
ZhangW.DongZ.ChangX.ZhangC.RongG.GaoX.et al (2018). Protective effect of the total flavonoids from Apocynum venetum L. on carbon tetrachloride-induced hepatotoxicity in vitro and in vivo. J. Physiol. Biochem.74 (2), 301–312. 10.1007/s13105-018-0618-0
149
ZhangR.LuoS.ZhaoT.WuM.HuangL.ZhangL.et al (2023a). Scavenger receptor A-mediated nanoparticles target M1 macrophages for acute liver injury. Asian J. Pharm. Sci.18 (3), 100813. 10.1016/j.ajps.2023.100813
150
ZhangC.TengY.LiF.HoW.BaiX.XuX.et al (2023b). Nanoparticle-mediated RNA therapy attenuates nonalcoholic steatohepatitis and related fibrosis by targeting activated hepatic stellate cells. ACS Nano17 (15), 14852–14870. 10.1021/acsnano.3c03217
151
ZhangQ.ToprakciogluZ.JayaramA. K.GuoG.WangX.KnowlesT. P. J. (2023c). Formation of protein nanoparticles in microdroplet flow reactors. ACS Nano17 (12), 11335–11344. 10.1021/acsnano.3c00107
152
ZhangJ. A.FengK.ShenW. T.GaoW.ZhangL. (2024a). Research advances of cellular nanoparticles as multiplex countermeasures. ACS Nano18 (44), 30211–30223. 10.1021/acsnano.4c09830
153
ZhangW.XuY.GuoR.ZhuangP.HongH.TanH.et al (2024b). Theranostic bottle-brush polymers tailored for universal solid-tumor targeting. ACS Nano18 (18), 11688–11702. 10.1021/acsnano.3c11755
154
ZhangL. F.DengW. Q.WangX. H.HuangQ.LiangS.DingZ.et al (2024c). Pathological microenvironment-remodeling nanoparticles to alleviate liver fibrosis: reversing hepatocytes-hepatic stellate cells malignant crosstalk. Adv. Sci. (Weinh)12, e2408898. 10.1002/advs.202408898
155
ZhangC.TengY.BaiX.TangM.StewartW.ChenJ. J.et al (2024d). Prevent and reverse metabolic dysfunction-associated steatohepatitis and hepatic fibrosis via mRNA-Mediated liver-specific antibody therapy. ACS Nano18, 34375–34390. 10.1021/acsnano.4c13404
156
ZhangL. F.DengW. Q.HuangQ. W.ZhangJ.WangY.ZhouT.et al (2024e). Vicious cycle-breaking lipid nanoparticles remodeling multicellular crosstalk to reverse liver fibrosis. Adv. Mater36 (16), e2311474. 10.1002/adma.202311474
157
ZhaoC.LiZ.ChenJ.SuL.WangJ.ChenD. S.et al (2021). Site-specific biomimicry of antioxidative melanin formation and its application for acute liver injury therapy and imaging. Adv. Mater33 (34), e2102391. 10.1002/adma.202102391
158
ZhaoY.HuK.WangF.ZhaoL.SuY.ChenJ.et al (2024). Guanidine-derived polymeric nanoinhibitors target the lysosomal V-ATPase and activate AMPK pathway to ameliorate liver lipid accumulation. Adv. Sci. (Weinh)12, e2408906. 10.1002/advs.202408906
159
ZhengJ.GeH.ZhouD.YaoQ.LongS.SunW.et al (2023). An activatable prodrug nanosystem for ultrasound-driven multimodal tumor therapy and metastasis inhibition. Adv. Mater35 (47), e2308205. 10.1002/adma.202308205
160
ZhuX.LiT.WangQ.YanK.MaS.LinY.et al (2024). Dual-synergistic nanomodulator alleviates exosomal PD-L1 expression enabling exhausted cytotoxic T lymphocytes rejuvenation for potentiated iRFA-Treated hepatocellular carcinoma immunotherapy. ACS Nano18 (47), 32818–32833. 10.1021/acsnano.4c11257
Summary
Keywords
nanoparticles, hepatic cells, hepatic sinusoids, liver targeting, liver diseases
Citation
Peng M, Fang F and Wang B (2025) Nanoparticle technologies for liver targeting and their applications in liver diseases. Front. Bioeng. Biotechnol. 13:1661872. doi: 10.3389/fbioe.2025.1661872
Received
08 July 2025
Accepted
29 September 2025
Published
23 October 2025
Volume
13 - 2025
Edited by
Huirong Lin, Harvard Medical School, United States
Reviewed by
Raj Hazra, North Dakota State University, United States
Mitra Hosseini, University of South Australia, Australia
Updates
Copyright
© 2025 Peng, Fang and Wang.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Bowen Wang, 1491867642@qq.com
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.