Cancer is one of the major causes of mortality globally, and if a unique and adaptable anticancer platform is not created, it may account for 70% of all deaths over the next 2 decades (Dai et al., 2017). As per CA: A Cancer Journal for Clinicians, approximately 19.3 million cancer patients were diagnosed, and approximately 10 million deaths were reported in 2020 (Sung et al., 2021). It is estimated that cancer incidences will worsen in the upcoming years by increasing the number of cancer-related deaths to 13.1 million by 2030 (Chaturvedi et al., 2019).

Nanotechnology contributed enormously in cancer therapy and opens unique paradigm to address issues with existing chemotherapeutic agents (Bae et al., 2011). Nanomedicines have vast applicability in the diagnosis, and treatment of disease. It is a painless therapy that improves human health and can be used as a molecular tool for specialized medical interventions at the molecular level. Nanosystems have been used in the last 10 years for a variety of purposes, including drug supply (Goldberg et al., 2007; Ferrari, 2010), tissue regeneration (Goldberg et al., 2007), detection at the molecular level, molecular imaging (Godin et al., 2011; Hu et al., 2011), and direct therapy of various cancers, such as melanoma, lung cancer, and breast cancer (Gazeau et al., 2008; Mamo et al., 2010).

Theranosis is an important tool in efforts to apply precision medicine in clinical practice, which uses imaging agents to target diseases at the molecular level while combining therapy and diagnostics. Cancer theranosis is proven to be incredibly helpful for both doctors and patients. The basic objective of nanotechnology is to enable nanoparticle-based agents to efficiently and selectively distribute payload, while avoiding toxic manifestation, as well as to reliably track noninvasively delivered therapeutic efficacy over time. The designed theranostic agents may be stimuli-responsive, targeted, or nontargeted. Targeted theranostic carriers incorporate a targeting ligand that can adhere to the receptors overexpressed in tumors. Currently, nanoconstructs are a promising approach to cancer treatment, and they are generated by combining nanoparticles (NPs) with ligands. They have a simple design, geometry, and stability, that can be delivered either actively or passively. Nanoconstructs overcome the drawbacks of conventional cancer therapies, such as toxicity and untoward biodistribution. However, they suffer from some known limitations, such as biocompatibility, uneven distribution, toxicity and lack of precision. To address these issues, the concept of autonomous and nonautonomous drug delivery was introduced in which the blood flow parameters and tumor microenvironment (TME)-related factors were taken into consideration. This review covers the fundamental aspects of the importance, effect, and potential of nanoconstructs while focusing on the most recent advancements of nanoconstructs in cancer diagnosis and therapy.

Cancer is a state in which a few cells of the body multiply uncontrollably and spread to other parts of the body. DNA damage, the major contributory factor for cancer, dysregulates various mechanisms that turn into specific malignant diseases. An unhealthy lifestyle and age has a significant influence on cancer occurrence (Wu et al., 2018; Quazi, 2022) Chikara et al. have reported that 19.3 million new cases of the cancer and more than 10 million deaths were reported in 2020, in worldwide (Chhikara and Parang, 2022). In the US, 1.9 million new cases and 609,360 deaths were reported in 2023 (Siegel et al., 2022).

Defective genetic changes or mutations in any of the listed genes, such as cytochrome P450 (CYP19, CYP2D6, CYP1A1), S-transferase (e.g., GSTM1, GSTP1), BRCA1/2, ATM, NBS1, PTEN, checkpoint kinase 2 (CHEK2), BRCA1 interacting protein (BRIP1), Nibrin (NBN), partner and localizer of BRCA2 (PALB2), RAD51C, RAD51D, malignant ovarian epithelial (MRE11A), Fanconi anemia, complementation group M (FANCM), tumor protein (p53), RAD50, BRCA1-associated ring domain (BARD1), alcohol, one-carbon metabolism genes (e.g., ADH1C, MTHFR), genes associated with DNA repair (XRCC1, XRCC3) and cell signaling receptors such as ER(Estrogen receptor), PR(Progesterone receptor), TNF-α(Tumor necrosis factor – α), may also contribute to the development of cancer (Easton et al., 2015; Walsh, 2015; Neidhardt et al., 2017). Furthermore, tumor heterogeneity, the TME, CSCs(Cancer stem cells), and epigenetics are factors responsible for the development of cancer, which may be accompanied by the development of chemotherapeutic resistance and recurrence associated with cancer (Jain et al., 2020).

The TME plays an important role in the development and poor prognosis of cancer (Baghban et al., 2020). The TME is highly heterogeneous in nature, and diverse cell populations make it more complex. The TME is highly associated with alteration or remodeling of the extracellular matrix (ECM), immune cells and other cellular processes in the development of drug resistance and relapse (Deepak et al., 2020). Tumor-associated markers such as tumor-infiltrating lymphocytes (TILs), tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs) and cancer-associated adipocytes (CAAs) are related to immune/tumor interactions, which contribute to the development of chemoresistance. Consistent tumor growth creates a hypoxic zone, acidic pH, and an anaerobic environment in the tumor mass (Lee and Griffiths, 2020). At the metastatic stage of cancer, chemotherapy is often not a promising therapy that will give a selective and broader response to patients (Jain et al., 2020).

Immunotherapeutic drugs have shown excellent growth by not only being the treatment for primary level cancer but also in avoiding metastasis and decreasing recurrence rates (Mahapatro and Singh, 2011). However, autoimmune problems are a main adverse effect of immune therapy. Furthermore, studies show that immune therapy is not as efficient for tumor cells as lymphoma (Kroemer and Zitvogel, 2018). A unique ECM is created by cancers that immune cells find difficult to infiltrate (Rosenberg et al., 2008). (Rosenberg et al., 2008). There are different types of immunotherapy for cancer, such as immune checkpoint inhibitors, T-cell transfer therapy, monoclonal antibodies, and vaccines. Immune checkpoints such as CLTA-4 and PD-L1 bind with other proteins of tumor cells and communicate with the immune system to allow for cancer development. Hence, various checkpoint inhibitors are used, such as PLGA-ICG-R837 for anti-CTLA4, and chimeric antigen receptor-mediated nanomedicines, which targets T cells (Cremolini et al., 2021).

‘Nanoconstructs’ are two-component structures made of a ‘hard’ nanoparticle core and a ‘soft’ shell of biomolecular ligands that are often used for targeted applications drug delivery (Dam et al., 2014). Nanosystems contain the active cargo and carrier for the delivery of drugs, which are preserved, transported over biological barriers, and then released as payloads (Allen and Cullis, 2004). The primary benefits of nanoparticle-based chemotherapy are the rise in treatment specificity, increasing drug deposition at the targeted region, and lowering peripheral toxicity (Schmidt, 1990). The nanoconstructs should be designed in such a way that they can retain a variety of agents on the surface or inside its core to form an ideal tool for combination therapy. After the administration of nanoconstructs, their ultimate fate depends not only on the surface chemistry but also on the whole vasculature, which includes pressure, velocities, and heterogeneities in tissues. Hence, to determine whether the nanoconstructs reached the walls of vessels or persisted in blood, a computational modeling technique was used based on 4S parameters (size, shape, surface and stiffness) (Başağaoğlu et al., 2013; Coclite et al., 2017). Therefore, computational methods are used for complex phenomena, and designing optimal nanoconstructs for biomedical applications. (Cervadoro et al., 2018).

Cancer therapy is a novel intervention that offers potential benefits to both physicians and patients. This system incorporates diagnostic capabilities aligned with targeted delivery for real-time monitoring of cancer therapy (Ryu et al., 2012). Cancer theranosis depends on the depiction of different phenotypes at the cellular level detected by theranosis agent at the targeted tumor location, allowing for cancer therapy and observation of the theranostic compounds (Table 2).

Nanotechnology has been identified as a possible option in cancer diagnosis and therapy. The majority of organic (polymer/lipids/dendrimers/liposomes, etc.) as well as inorganic NPs (metallic NPs/carbon nanotubes/quantum dots, etc.) imparted with imaging, treatment, and targeting abilities. The application of theranostic NPs in chemotherapy, photothermal therapy, siRNA/miRNA delivery, and other cancer treatments is currently the subject of substantial research.

The Enhanced Permeability and Retention Effect (EPR) effect is a process that is explained by the hyperpermeation and extended retention of biomolecules encapsulated in nanocarriers, such as lipoproteins, hormones, and albumins, retained in solid tumors which contains leaky vasculature, elevated endothelial macromolecule transcytosis, and a lack of functional lymphatic drainage inside its interstitium (Figure 3).

To obtain EPR effect-based selective tumor deposition, low extravasation of normal-type tissue and renal clearance are needed. The nanoconstructs’ reduced particle size, which is lower than tumour vascular permeability, allowed them to easily pass through and produce the EPR effect (600–800 nm). However, the nanoconstructs have the bigger particle size than the pore of blood capillary (6–12 nm) and renal filtration (5–6 nm), influences the targeting of NPs (Choi et al., 2009).

Multiple tumors may develop tumor interstitium with different ECM (e.g., fibrin, fibronectin, hyaluronan collagen, and proteoglycans), tumor parenchyma and stroma cell compositions due to variations in the tumor type and stage. The variations in physical rigidity and pressure ranges may affect the distribution and transport of nanoconstructs in the tumor, which may further affect their therapeutic efficacy (Swartz and Lund, 2012; Perry et al., 2017). Hepatocellular carcinoma, Kaposi sarcoma, renal cell carcinoma, and cancer of the neck and head (Regev et al., 2005) are known to be high-level EPR tumors, whereas pancreatic ductal carcinoma and prostate cancer (Maeda, 2015) are referred to as low-EPR tumors.

There are other factors that hinder nanoconstructs distribution and deposition in tumors other than drawbacks of the EPR effect, such as biological and physical hurdles in delivering an adequate dosage of a therapeutic drug to the targeted site of the tumor. (Bae and Park, 2011). After intravenous delivery, nanoconstructs undergo multiple events, such as adsorption of proteins, diffusion of particles, aggregation, shear force destruction and hydrolysis. (Florence, 2012; Lazarovits et al., 2015). These types of events influence the number of nanoconstructs that eventually reach the tumor. The degree to which these events impact nanoconstructs tumor accumulation may vary depending on the physicochemical characteristics of the nanoconstructs (Gould et al., 2015). Another challenge is incorrect perceptions derived from the selection of in vivo models at the preclinical stage. In vivo studies performed on animal-derived cancer models do not show a resemblance to human cancers. The ratio of a person’s body weight to their tumor’s size is comparatively lower than those in animal models. As a result, it is not a surprise that the amount of nanoconstructs reaching the tumor sites in humans is probably less than the requisite therapeutic range.

Despite the issues outlined above, several ways to address these problems may facilitate nanoconstructs penetration and deposition into tumors. A generic classification adapted to facilitate drug release and enhance the effectiveness of nanoconstructs comprises autonomous and nonautonomous systems of drug delivery.

Nonautonomous cancer treatment was classified as actively and passively aimed nanoconstructs. The modification of TME with the help of NPs can be considered a promising approach for the management of cancer (Jia et al., 2021). It is an established fact that cancer cells survive in an oxygen-deficient environment known as a hypoxic environment. The integral switch to switch off mitochondrial energy production is independent of ATP and oxygen supply and switches on the alternate pathways to produce energy in oxygen-deficient environments. Thus, by stopping the cells from switching on the alternate pathway, cancer growth can be controlled. To make this possible, many NPs are coming into play. For example, the mitochondrial chaperone TRAP-1 is structurally and functionally similar to the Hsp90 family of proteins, which have the potential to switch on alternate pathways for energy production in tumor cells. Hence, nanocarriers to deliver TRAP-1 inhibitors were developed in which iron oxide nanoparticles (IONs) were conjugated to the Hsp90 inhibitor geldanamycin (GA) and the mitochondria localization signal (MLS) peptide to enable selective tumor targeting (Amash et al., 2020). One of the recent studies examined the impact of the surface curvature of nanoconstructs on endosomal pathways using CpG (cytosine-phosphate-guanine)-conjugated spiky and spherical gold NPs. Administration of spherical NPs followed by spiky NPs prompted the production of larger late-stage endosomes. The outcomes from this research demonstrate a possible impact of nanoconstructs design on intracellular fate (Lee et al., 2022).

The autonomous delivery systems are described as ‘therapeutic missiles’, as they can transport the nanoconstructs to the target regardless of the flow of blood and its direction. Recent advancements in autonomous-type delivery systems indicate that biomimetic-type delivery and biohybrid bacteria have the desired therapeutic potential (Yu et al., 2020). In one report, a nanomedicine-loaded bacterium that can propel itself was used to cure cancer. This autonomous swimmer destructs itself and delivers the anticancer medication at the targeted site (Figure 4). Incubation and electroporation were two methods that were utilized for introducing NPs into the bacteria, where incubation was found to be less effective than electroporation. More precisely, DOX-containing 100-nm liposomes were injected into motile bacteria (Salmonella) (Zoaby et al., 2017). When the bacteria enter cancer cells, the drug is internally released to kill the cancer cell. Salmonella was chosen over E. coli to build the nanoswimmer platform due to its higher velocity in the TME and its capacity to target tumors and penetrate triple-negative cancer cells. In general, the TME favours bacterial motility, which is dependent on glucose and pH (Pontier-Bres et al., 2012).

The sciences of nanomedicine and artificial intelligence are two highly powerful tools for advancing the cause of personalized medicine. Drug synergy is a constant problem for cancer patients receiving any type of drug administration because it depends on time, dose, and patient at any point in the therapeutic process. Furthermore, due to significant intratumor and interpatient heterogeneities, it is difficult to rationally design diagnostic and therapeutic delivery systems and study their outcomes. Closing these gaps and improving the accuracy of diagnosis, drug delivery, and therapy requires the integration of artificial intelligence technologies (especially data mining, neural networks, and machine learning) (Soltani et al., 2021).

An innovative statistical method for developing controlled release drug delivery systems(CRDDS) is the artificial neural network (ANN). When there is no obvious functional dependence between the inputs and outputs, it is one of the best methods to be relied upon. ANNs can also be used to model complex biological data and nonlinear systems (Cheung and Rubin, 2021). Other uses for ANNs include cancer classification, predicting protein secondary structures, and solving multiresponse and multivariate system problems (Bi et al., 2019). The relationship between process variables, formulation, and CRDDS drug release profiles is not implicit or linear. As a result, related networks can be used in conjunction with other ANN model types. These ANN models can be used to depict the relationship between process variables, formulation, and response, such as in vitro drug release patterns (Patel and Patel, 2016). In comparison to conventional therapies, the application of AI (Artificial Intelligence) in the formulation of nanotheranosis can be a great benefit for better positioning of diagnostic and therapeutic substances into the body. If imaging agents and medications need to be loaded into a certain carrier, predictive AI algorithms can be utilized to forecast encapsulation efficiency (EE%) (Soltani et al., 2021). For instance, a QSPR model was used to predict, with greater than 90% accuracy, whether molecules may be loaded into the carrier based on the circumstances of the encapsulation process and their chemical makeup. A similar method can be employed to evaluate the cytotoxicity of other NPs and to assess the impact of surface modification on biocompatibility. When talking about medical imaging, it is important to consider how AI can contribute to image analysis. By using the aforementioned methods in imaging from nanos, one can better comprehend the therapeutic efficacies and particle biological dispersion patterns (Xu et al., 2019).

Currently, Nanorobotics is the emerging technology of constructing robots in the nanometric scale, which are creating a niche in the biomedical field (Raaja et al., 2016). In similar line, DNA based nanomaterials controlled by aptamer encoded logic gate can be utilized as autonomous delivery systems (Douglas et al., 2012). Since DNA is a natural substrate for computing, it has benefitted a diverse set of logic circuits and robotics (Katsnelson, 2012). In this context, DNA origami can be utilized to develop nanorobots which can intercommunicate and can be activated to release the drug cargo at the targeted site. This will allow the real time monitoring, faster delivery and computer assisted drug delivery (Khulbe, 2014; Devasena Umai et al., 2018).

There are multiple other examples in which DNA nanorobots can target HER2-positive breast cancer cells to induce apoptosis (Ma et al., 2019), deliver drug cargo to the cancer tissue mediated by nucleolin targeted therapy (Li et al., 2018), identification of cancer biomarkers (Mirzaiebadizi et al., 2022) and act as biosensors to allow the detection of target oligonucleotides and miRNAs (Domljanovic et al., 2022).

Conventional drug delivery systems for anticancer therapy frequently lack the ability to target medications to certain organs or tissues of interest (tumors), as well as the ability to track or image the in vivo fate and assess the effectiveness of drug administration. Imaging tumor regression in patients after targeted therapy X-ray, CT or radiography, will be considered a separate intervention altogether. Multiple objectives can be accomplished with a single dose by co-administering the image guided molecules incorporated in the delivery system. It may facilitate evaluation of extent of drug targeting, sites of localization, excretion, and imaging (Iyer et al., 2012).

In one of the reports, PSMA aptamer-conjugated DOX-loaded iron oxide NPs were developed that could be used as theranostic agents in prostate cancer. These systems detect prostate cancer sites (by MRI) and even deliver the drug DOX to the target tissue (Yu et al., 2011).

Treatments that comprise biocompatible NPs could provide precise optical/MR imaging and treatment to cells that overexpress folate receptors. The co-encapsulation of DTX and NIR dyes into NPs, which are novel additions to nano delivery systems for the detection, diagnosis, and treatment of malignancies, was also produced using a modified solvent diffusion approach (Santra et al., 2009).

In one such approach, light-activated theranostic NPs made up of PEG-modified polyacrylamide combined with iron oxide NPs and photofrin, a strong photosensitizer. were used for the imaging and photodynamic treatment of brain malignancies., F3 peptide was used as a ligand to specifically target nucleolin receptors present on endothelial cells and tumor cells. This system showed antitumor effects in a rat brain tumor model for brain targeting (Reddy et al., 2006).

Another method relies on bifluorescence resonance energy transfer (Bi-FRET) technology, which was applied to quantum dot (QD)-aptamer conjugates for simultaneous tumor imaging and DOX delivery. A functional RNA aptamer was attached to the surface of quantum dots and DOX was embedded in the aptamer., By triggering the fluorescence of QDs, this nanosystem was able to visualize drug delivery as well as to target prostate cancer cells (Bagalkot et al., 2007).

In continuation, pH-responsive polymeric micelles were developed with an aim of in vivo imaging and photodynamic therapy of tumors (Zhong et al., 2019), where, methoxy PEG was conjugated with a pH-sensitive polymer, poly (b-amino ester). Self-assembly of the block copolymer with protoporphyrin IX, a radiosensitizer, led to the formation of nanomicelles. pH-responsive release of protoporphyrin IX was observed in the acidic environment of tumors. Clear tumor accumulation and complete tumor ablation were observed by fluorescence imaging using tumor-bearing mouse models. Thus, these systems show great potential as photo dynamic theranosis (Koo et al., 2010).

Nanoconstructs designed for theranostic applications in cancer offer improved detection, precise delivery of drug cargo to tumors and fewer devastating effects on healthy organs. Additionally, imaging approaches can evaluate the effectiveness of medications in real time by using customized probes. Understanding the TME and cancer-associated events with the help of computational modeling will enable the development of nanoconstructs with desired attributes. A plethora of nanotechnology-based platforms have been explored for theranostic applications, including nanomaterials from organic and inorganic origins. Exogenous and endogenous stimuli play vital roles in controlling drug release and augmenting the autonomous and nonautonomous mechanisms of targetability. The full potential of DNA origami, nanorobots, artificial intelligence and machine learning has yet to be explored for the development of nanoconstructs for cancer theranosis. Although enormous progress has been made in the development of nanoconstructs for theranostic application, very few of them could advance to the clinical phase of investigation. However, the solution always lies in advanced nanomaterials, which will open up a new vista for the development of multimodal NPs equipped with better diagnostic and therapeutic capabilities. The desired outcomes through the advent of nanotechnology can only be facilitated by conducting multidisciplinary studies in a large cohort of patients.