Vrinda Gupta,1 Dinesh Kumar,2 Sonia Gupta,3 Rajni Tanwar,4 Nicky Kumar Jaiswal,5 Md Moidul Islam,5 Shivani Singh,6 Neeraj Choudhary,7 S Gowri,8 Thomas J Webster,9– 12 Md Faiyazuddin13

1The ICFAI University, Baddi, Himachal Pradesh, 174103, India; 2Department of Pharmaceutics, GNA School of Pharmacy, GNA University, Phagwara, Punjab, India; 3Department of Pharmaceutics, Swami Devi Dyal Group of Professional Institute, Barwala, Panchkula, India; 4Department of Pharmaceutics, Department of Pharmaceutical Sciences, Guru Jambeshwar University, Hisar, Haryana, India; 5Department of Pharmaceutical Science, School of Pharmacy, Desh Bhagat University, Fatehgarh Sahib, Punjab, India; 6Department of Pharmacology, School of Pharmaceutical Sciences, Jaipur National University, Jaipur, Rajasthan, India; 7Department of Pharmacognosy, GNA School of Pharmacy, GNA University, Phagwara, Punjab, India; 8PG & Research Department of Physics, Cauvery College for Women, Affiliated to Bharathidasan University, Tiruchirappalli, Tamil Nadu, 600018, India; 9School of Health Sciences and Biomedical Engineering, Hebei University of Technology, Tianjin, People’s Republic of China; 10School of Engineering, Saveetha University, Chennai, Tamil Nadu, India; 11Program in Materials, UFPI, Teresina, Brazil; 12Division of Pre-College and Undergraduate Studies, Brown University, Providence, RI, USA; 13Centre for Global Health Research, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India

Abstract: Cancer continues to pose a global health challenge, with conventional therapies often limited by non-specific toxicity, drug resistance, and an inadequate therapeutic index. Nanotechnology offers transformative opportunities by enabling targeted drug delivery, improved pharmacokinetics, and integrated diagnostic-therapeutic platforms (termed nanotheranostics). This review highlights key nanocarrier systems including liposomes, polymeric nanoparticles, dendrimers, inorganic nanostructures, carbon-based materials, extracellular vesicles, and hybrid platforms with a focus on human studies and clinical translation. Design strategies (such as passive and active tumor targeting, biomimicry, and stimuli-responsive release mechanisms) are discussed in the context of improving tumor selectivity and minimizing systemic toxicity. Recent innovations, including AI-supported nanomedicine design, smart nanorobots, and cell-mediated delivery systems, are also examined. Although multiple nano-formulations such as Doxil®, Abraxane®, and Vyxeos® have reached clinical use, challenges remain including large-scale manufacturing, regulatory pathways, long-term safety evaluation, and cost-effective global accessibility. This review provides a critical appraisal of current evidence, translational bottlenecks, and emerging opportunities to guide future nanomedicine development. Nanotechnology is poised to become a cornerstone of precision oncology, enabling personalized, safe, and effective cancer treatment paradigms.

Keywords: cancer immunotherapy, drug delivery, nanocarriers, nanotheranostics, oncology, precision medicine

Introduction

Cancer is still one of the most serious global health problems of the 21st century, and this disease kills almost 10 million people each year. GLOBOCAN 2024 indicates that there were approximately 20 million new cancer cases and 9.7 million cancer deaths in 2022 alone.1 The most frequent cancers include lung, breast, colorectal, prostate, and stomach, but the most frequent single type of cancer is lung cancer, causing approximately 1.8 million fatalities annually.2 By 2050, the number of cancer cases might top 35 million, for a total rise of 77%, with the sharpest rate of acceleration in low- and middle-income countries. Simultaneously, the nanomedicine oncology market is growing. Specifically, the nanomedicine market is expected to grow at a CAGR of ~11 to 12%, with the largest application in oncology.3 Today, cancer is the second most frequent cause of death in the world.4 The World Health Organization has estimated that by 2040, the global cancer burden could increase to 28.4 million new cases or 47% more new cases by the year 2020, which will largely be due to aging populations, lifestyle factors, environmental exposures and the emerging prevalence of oncogenic infections in some parts of the world.5 Cancer continues to cause high global mortality, and despite major advances in chemotherapy, radiotherapy, targeted therapy, and immunotherapy, many patients still experience limited benefits due to toxicity, resistance, tumor heterogeneity, and inconsistent treatment responses.6 Several FDA-approved nano-formulations, including Doxil®, Abraxane®, Vyxeos®, and NBTXR3, have already demonstrated advantages such as improved drug delivery, reduced systemic side-effects, and enhanced efficacy compared with conventional agents.7 These clinical outcomes highlight the growing role of nanotechnology in addressing unmet needs in cancer treatment and support its potential to advance safer, more precise, and personalized oncology care.8

Although decades of considerable scientific effort has taken place, traditional treatment practices, such as surgery, chemotherapy, radiotherapy, and immunotherapy, remain rather monumental tasks to overcome and eradicate cancer entirely and permanently.9 Although effective at killing rapidly dividing cells, conventional chemotherapeutic agents are widely non-specific and produce acute systemic and collateral damage to healthy tissues.10 The repeated use of such drugs can cause multidrug resistance (MDR) in many different ways, such as the overexpression of cancer cell efflux pumps, genomic mutation, and drug target variation, which considerably decrease the therapeutic effect over time.11 In a similar way, radiotherapy, despite a wide range of applications, can only be applied accurately when it comes to separating malignant tissues and the surrounding normal tissues, invariably leading to off-target treatment and permanent side effects.11 Although the recent introduction of immunotherapies, specifically using the patient’s own immune system, has revolutionized the way in which certain cancers are managed, issues like immune system evasion by cancer cells, patient heterogeneity in treatment response, high costs, and immune-related adverse events continue to serve as high barriers to their universal success. This enduring disparity between benchside to bedside has pushed the oncology community to reconsider the diagnosis, treatment, and vital surveillance of cancers.12 In recent years, precision oncology has created a paradigm shift, the grand objective of which is to match interventions with the genetic microenvironment and molecular traits of the patient-specific tumor. Bioimplants and more personalized therapies have been enabled by technological developments in high-throughput sequencing, multi-omics technology, and biomarker discovery.13 Nevertheless, these insights concerning precise drug delivery and real-time monitoring have yet to be translated to patients effectively, representing a considerable scientific and technical challenge.

For this transitioning field, the paradigm of nanotechnology has become a game changer to tackle most of these age-old challenges. Engineering nanoscale materials (usually less than 100 nm in at least one direction) allows researchers to develop multi-functional nanocarriers, not only protecting therapeutic agents against premature wear, but also increasing their delivery to the tumor destination via passive and/or active targeting. As an example, the enhanced permeability and retention (EPR) phenomenon, which indicates that leaky tumor vasculature permits nanoparticle (NP) entry and retention more easily than that of free small molecules, has been heavily applied for passive targeting.14 In the interim, active targeting schemes allow ligands with antibodies, peptides, and aptamers site-specific tumor-associated cell receptor binding, and offer better targeting to tumor cells, diminishing overall systemic toxicity.15 Nanotechnology platforms applicable to oncological processes have been developed broadly, and include liposomes, polymeric NPs, dendrimers, inorganic nanostructures (eg, gold NPs and iron oxide NPs), carbon-based nanomaterials (eg, carbon nanotubes and graphene materials), and biologically derived nanocarriers such as extracellular vesicles and exosomes.16 Most of these structures can be additionally designed to react to internal (pH, redox, enzymatic, etc.) or external (temperature, magnetic fields, light, etc.) cues, enabling the release of drugs in the tumor microenvironment (TME) in a time and controlled, on-demand fashion.17 In addition to drug delivery, loading diagnostic agents in nanocarriers has given rise to a new field, nanotheranostics, which has provided opportunities to both image and monitor cancer treatment, adaptively adjusting to a therapeutic response living in tandem with precision medicine. Promisingly, some nanomedicine preparations have already been used in clinical settings enhancing pharmacokinetics, minimizing side effects, and enhancing patient outcomes over conventional treatment methods. Among them, examples that one may recall are liposomal doxorubicin (Doxil-R) and albumin-bound paclitaxel (Abraxane-R).18

Nevertheless, despite such developments, serious impediments still exist that have to be overcome prior to the wide availability of nanotechnology-based cancer drugs for humans.19 Problematic questions of mass production, replicability, batch-to-batch variation, regulatory clearance routes, and long-term safety, as well as availability and fair accessibility, are also burning questions that demand cross-disciplinary cooperation and comprehensive translational approaches.20 The purpose of this review is to offer a critical and full overview of the existing and future perspectives of nanotechnology-based cancer treatments. We start by outlining key nanotechnology platforms being studied, with specific features, benefits, and drawbacks of each platform. Various tumor-targeting approaches are discussed next, such as passive accumulation, ligand-based active targeting, stimuli-responsive, and cell-mediated delivery platforms.21 Following this, we proceed to discuss therapeutic applications as diverse as traditional chemotherapy, radiotherapy adjuvants, photothermal therapy, photo dynamic therapy, immunotherapy, gene therapy, and multifaceted synergistic therapies. The convergence of precision and personalized oncology with nanotechnology is described, including omics-based design, biomarker-responsive systems, and newer directions, emphasizing nano-bioinformatics and artificial intelligence (AI)-aided formulation development.22 Additionally, we look at bridging preclinical validation to clinical use, emphasizing success stories, their current clinical trial status, regulatory parameters, consideration of good morals, and the pitfalls that should not be avoided when introducing safe and efficient applications. We conclude by providing a prospective outlook of the developments that are most likely to define the future of nanotechnology in cancer, with the notable mention of smart nanorobots, bioresponsive hydrogels, and adaptive AI-guided nanoplasts.23 Through a holistic and progressive view of the subject, this review aims to make researchers, clinicians, industry stakeholders, and policymakers aware of the paradigm-changing aspects of nanotechnology in the context of redefining cancer care over the decades to come.24

Nanotechnology Platforms in Oncology

Nanotechnology has introduced numerous platforms to overcome the shortcomings of traditional cancer treatment.25 All of these nanocarriers are different in terms of their constitution, plasticity in use, and method of enhancing anti-cancer drug delivery, targeting, and therapeutic effect. This section provides a description of the most notable nanotechnology platforms that are currently at the forefront of enhancing cancer diagnosis and treatment.26

Liposomes

Liposomes have been one of the most clinically proven nanoplatforms, yet recent developments have pushed them much even further than lipid vesicles. The next generation liposomes incorporate active targeting, duplex-purposed payloads, and active real-time imaging (making them smart theranostic platforms).27 The traditional clinical gold standard is liposomal doxorubicin (Doxil®/Caelyx®), which has been approved to treat multiple malignancies with a demonstrable usefulness in reducing cardiotoxicity. In addition to these new liposomal preparations, others are being tested to overcome multi-drug resistance (MDR) and tumor heterogeneity.28 As an example, ThermoDox® (NCT02181075) is a doxorubicin-loaded temperature-sensitive liposome that delivers its drug cargo upon exposure to mild hyperthermia and is in clinical trials to treat breast cancer in recurrent chest walls and hepatocellular carcinoma. On the same note, Marqibo® (Liposomal Vincristine) has been approved by the FDA to treat Philadelphia chromosome-negative ALL, and it is quite evident that drugs with poor pharmacokinetics (PK) can be rescued using liposomes.29 These state-of-the-art designs deploy stimuli-responsive shells that can degrade in acidic or enzymatic environments of the tumor microenvironment (TME). Other research groups are mixing liposomes and immune adjuvants to use as a nano vaccine platform to boost tumor immunogenicity. As an example, personalized neoantigen vaccines (n.b., BNT111, NCT04526899) are being tested as cationic liposome-based mRNA carriers. Moreover, the integration of liposomes with diagnostic agents (eg, gadolinium or fluorophores) and associated methodologies that allow image-guided drug administration are under development.30 There is also an effort to use biomimetic liposomes (such as liposomes coated in cell membranes, eg, cancer cell membranes or platelet membranes) to avoid being detected by the immune system and allow for a more sustained circulation in the body, which has been shown to be effective in preclinical experiments. Liposomes are, in general, incorporating more multi-stimuli, multi-functional smart vesicles, positioning themselves between conventional chemotherapy and more effective targeted, personalized, and image-guided oncology.31

Polymeric NPs

Polymeric NPs no longer merely provide a reservoir for a drug, but instead they are becoming much more advanced platforms that can co-deliver many therapeutics, and conquer chemotherapeutic-resistant cancer cells, even functioning as programmable micro-reactors within tumors.32 They are extremely versatile towards delivering a precision cancer therapy because of their tunable size, surface chemistry, and degradation profiles. Generally, such polymers are FDA-approved including PLGA (poly(lactic-co-glycolic acid)) and PEGylated or stainless-steel natural polymers such as chitosan or hyaluronic acid.33 Due to their predictability in terms of release kinetics and biocompatibility, these biodegradable materials have been developed into a number of polymeric NPs which have moved into clinical evaluation. Among them is BIND-014, which is a docetaxel-loaded, prostate-specific membrane antigen (PSMA)-directed PLGA NP, that has entered Phase II trials (NCT01812746).34 Despite the commercial failure of the original company that developed these materials, clinical results demonstrated increased tumor localization with diminished systemic toxicity, confirming the idea of ligand-targeted polymeric NPs. Further, there has been a new trend to concentrate on dual-delivery techniques. An example is the preclinical testing of PLGA NPs co-encapsulating paclitaxel with MDR1 siRNA in an attempt to silence multiple drug-efflux genes to induce chemo-sensitivity in chemo-resistant tumors. Another trend includes pH/redox dual-responsive polymeric micelles that remain intact when exposed to acidic tumor vicinities and conditions of high glutathione concentrations but will release a drug in a site-specific manner.35

Recently, there have been bioresponsive polymers that can change according to the TME stimulus. As an example, the overexpression of CD44 by cancer cells may be used to actively target hyaluronic acid-coated NPs, as was done in early-stage studies of breast and lung cancers. In addition to delivery, polymeric NPs are increasingly finding use as nanoreactors, loaded with catalytic payloads, which produce cytotoxic reactive oxygen species within cancer cells, a developing line of research in nanocatalytic cancer therapy.36 Polymer design based on AI is also being researched to simulate the ideal architecture to implement multi-agent loading situations and an accurate release profile. Seen cumulatively, polymeric NPs have not only existed as passive carriers, but they are also becoming smart and bioresponsive, programmable platforms that can carry drugs, genes, or immunomodulators and target multiple hallmarks of cancer.37

Dendrimers

Dendrimers can be distinguished by their accurate tree-like branched geometry that provides extraordinary control over size, shape, and surface functionality. Such structural specificity enables dendrimers as not just high-capacity reservoirs of drugs, but also versatile vehicles of genes, imaging probes, and therapeutic adjuvants, making them excellent candidates as truly multifunctional theranostic platforms. PAMAM (polyamidoamine) is the most well-defined dendrimer system to date and has thus been extensively studied as an agent useful in cancer therapy in light of its biocompatibility and functional groups on the surface (namely, amine groups) that can be used to allow for multi-site functionalization.38,39 Although there is still no FDA-approved dendrimer-based anticancer drug, a number of translational studies are underway at the preclinical, early human stage. AZD0466, or an inhibitor of BCL-2/xL, is one of these hopeful candidates since it was delivered within a dendrimer-based scaffold to enhance solubility and ligand release. AZD0466 entered into a clinical trial for hematological malignancies (NCT04214093), demonstrating the possibility to rescue poorly soluble, otherwise complex small molecules with dendrimers.40 Dendrimers have also been considered for gene delivery . The fourth-generation PAMAM dendrimer-siRNA and CRISPR/Cas9 elements were delivered successfully and showed powerful gene downregulation in preclinical solid cancer experiments, treating MDR and overexpression of oncogenes through improved intracellular uptake over naked nucleic acids.

Dendrimer surface functionalization is also quickly moving beyond the state of the art where investigators are functionalizing dendrimer terminals with targeting ligands, eg, folic acid against ovarian cancer or RGD peptides against integrin-overexpressing solid tumors. Dual targeting dendrimers (eg, tumor cells and tumor vasculature at the same time) are now in preclinical testing. Stimuli-responsive dendrimers that break apart in acidic or reductive tumor micro conditions, provisionally guarantee on-demand release of drugs with minimum leakage into non-target environments, have also been a recent trend. Occasional dendrimer structures are under development as a co-delivery depot of MRI contrast agents, resulting in the real-time tracing of biodistribution and therapeutic effects, representing a step towards personalized adaptive dosing.41 A central concern of safety has been maintained because cationic dendrimers can cause membrane disruption at high levels. This is currently being overcome through PEG or zwitterionic coatings to cover surface charges. In general, dendrimers are no longer considered simple, immobile, drug-carrying systems but have been upgraded to intelligent, multi-use, and stimuli responsive transporters in which such drugs are delivered to locations that require them, and in which early-stage clinical trials, such as the AZD0466 (NCT04214093), act as precursors to their future integration into precision oncology.

Inorganic NPs (Gold, Iron Oxide, and Quantum Dots)

Inorganic NPs present unusual optical, magnetic, and catalytic features that allow them to transcend well beyond the realm of conventional drug delivery. These structural versatilities have made these materials multifunctional agents for targeted therapy, hyperthermia, imaging, and combined theranostics.42 One of these pillars include gold NPs (AuNPs) that have strong biocompatibility, tunable size and shape, and a unique surface plasmon resonance that permits photothermal and photodynamic applications. Silica-gold nanoshells, branded as AuroLase 650, were loaded with near-infrared light and used to merge into localized heat to destruct solid tumors in cancer, which entered a pivotal Phase I trial for head and neck cancers (NCT00848042).43 A newer generation of gold nanoshells are increasingly being hybridized with immunoadjuvants to achieve systemic anti-tumor immunity after ablation, turning local ablation into a systemic vaccine-like effect, but despite best-efforts of regulatory bodies to stay apace with progress, due to issues of scalability and control of heat-dosing, such materials have yet to be used clinically.

Some iron oxide NPs (IONPs) have been FDA certified as MRI contrast agents (eg, Ferumoxytol in iron deficiency anemia containing off-label utilization in imaging). They have the potential to be used in drug delivery-based image guidance and for magnetic hyperthermia, in which particles are heated by an alternating magnetic field to kill tumor cells.44 NanoTherm Planisilane-coated iron oxide NPs, bound to a localized magnetic hyperthermia therapy, have been approved by the European regulatory authority with recurrent glioblastoma therapy and prostate cancer and are still in clinical trials (eg, NCT02033447).45

Quantum dots (QDs) are novel semiconductor nanocrystals, which possess unique fluorescence emission, that have been recognized as next-generation imaging probes for the early detection of a tumor, during surgical intervention.46 In contrast, their translation to the clinic has lagged behind because of fears of heavy metal toxicity (eg, cadmium cores) with recent research focussing more on carbon and silicon-based cadmium-free QDs for enhanced biocompatibility. One such promise involves the use of carbon-dot hybrid systems which are a combination of tumor-specific imaging with drug loading and reactive oxygen species (ROS) based photodynamic therapy of triple negative breast cancer in preclinical studies.

More recent developments involve combining inorganic NPs with biomimetic coatings; eg coating gold NPs with cancer cell membranes to improve tumor homing and immune system evasion.47 The next upcoming approach to watch is the production of hybrid nanostructures, eg, gold-iron oxide corediff-shell particles, which integrate magnetic resonance imaging with plasmonic photothermal therapy in one platform. Difficulties persist with regard to bio persistence and routes of clearance of such inorganic materials over the long term. Researchers are overcoming this by engineering ultrasmall inorganic NPs (<10 nm) with the ability to be cleared through the kidneys by renal filtration, thereby reducing the possibility of buildup and development of chronic toxicity. Overall, inorganic NPs are good examples of how physical characteristics at the nanoscale can be used to achieve exact tumor destruction, imaging without needle and hybrid treatment, crossing the line between diagnosis and therapy.48 Current examples of ongoing clinical trials with AuroLase 106 (NCT00848042) and NanoTherm (NCT02033447), confirm their clinical relevance and the growing promise of nanotheranostics.

Carbon-Based Nanostructures (Carbon Nanotubes and Graphene)

Nanomaterials made especially of carbon (such as carbon nanotubes (CNTs) and graphene derivates) have received attention because of their large surface area and controllable functional groups, as well as having superior electrical and photothermal capabilities. Carbon nanostructures can carry biomolecules and contrast image in contrast to many fully dense organic nanocarriers. They make simultaneous delivery, imaging, and controlled external activation possible allowing them to be at the forefront of smart nanomedicine. CNTs refer to cylindrical graphene sheets of single (SWCNT) or multiple (MWCNT) walls.49 They are naturally shaped like needles enabling for efficient cell uptake and work as nanoneedles to inject therapeutic agents (drug, genes, or imaging agents) directly into the cytoplasm skipping the conventional endocytosis routes. Yet clean CNTs can be highly toxic because of hydrophobic agglomeration and remaining unreacted metal catalysts, thus, large bodies of research have been directed at CNT functionalization to decrease toxicity.50 Newer developments have centered on functionalizing CNTs with hydrophilic polymers (eg, PEGylation) or with targeting ligands to limit off-targeting and increase tumor specificity. As an illustration, folate-conjugated PEGylated SWCNTs were found to considerably accumulate in folate receptor-positive ovarian cancer cells. Although none of the CNT-based oncology drugs are in clinical trials presently, preclinical programs exhibit potent tumor ablation with a combination of CNTs and near-infrared (NIR) light in photothermal therapy.

Graphene oxide (GO) and reduced form (rGO) have plenty of oxygen-containing groups which provide high-capacity drug loading, surface modification, and stimulated release.51 GO-based nanosheets have shown synergy with chemotherapy and photothermal therapy: they can convert NIR light into heat (greatly enhancing cytotoxicity). As an example, PEGylated GO conjugated with doxorubicin possessed increased efficacy against breast cancer xenografts by avoiding efflux pumps and anytime release. Meanwhile, an important translational thrust has been focussed on hybrid carbon-based composites – combining GO or CNTs with metals (gold, iron oxide) or polymers – to form multifunctional constructs serving as combined therapeutic and imaging agents.52

A potentially interesting current research area involves synthesizing graphene-quantum dot hybrids to delineate tumor margins in real-time in an intraoperative setting. Their safety and clearance have been among the major bottlenecks for clinical translation. Recent research is overcoming this by designing ultrasmall carbon dots (<10 nm) capable of remaining highly photoluminescent while being eliminated renally. Further, biomimetic methods, ie, covering CNTs or GO with cancer cell membranes, have also been investigated to increase immune cell evasion, thus, extending circulation.53 NA is yet another innovation, under AI guidance. Functional group densities and aspect ratios are being optimized by machine learning, at a desirable drug-loading density and biocompatibility; a trend that promises rapid standardization for improving regulation. CNTs, along with other nanostructures based on graphene, are a potent family of multifunctional, externally trigger response carriers that are ready to address problems of drug resistance, tumor recidivism, and live tracking situations. They are not currently being tested for oncology but, with a strong preclinical pipeline, are virtually the next generation of precision nano-intervention platforms.54

Extracellular Vesicles / Exosomes

Extracellular vehicles (EVs) and especially exosomes have become nanocarriers of a natural origin, demonstrating distinct benefits impossible to achieve in synthetic systems. Formed as vesicles released by nearly all cell-types, exosomes (30–150 nm) are naturally involved in transporting proteins, lipids, and nucleic acids, thus crucial to cell-to-cell communication; a capability in recent years being introduced to bioinspired cancer nanotherapies. Exosomes possess labile biocompatibility, low immunogenicity and native homing skills that tend to recreate the molecular portrait of cells.4,55 This offers potential as tumor-specific delivery vehicles of both small molecules and nucleic acids, and even CRISPR/Cas9 gene-editing substrates. Their ability to penetrate biological barriers such as the blood-brain barrier (BBB) is one of their strongest potentials that make EVs good candidates for the treatment of brain cancer, such as glioblastoma. Among the clinical studies, a prominent EV example is ExoSTING that uses a STING agonist against cancerous immunity.56 ExoSTING is currently under Phase I development against advanced solid cancers or lymphoma (NCT04592484), which is one of the earliest clinical efforts to use exosomes to re-educate the immune system.57

Despite their strong therapeutic promise, exosomes and genetically engineered exosome-mimics (GEM) face practical barriers for clinical scale-up. Current limitations include low synthesis yield and the absence of standardized, high-throughput GMP-compliant isolation and purification platforms.58 Ultracentrifugation, precipitation, and size-exclusion methods often result in heterogeneous vesicle populations, variable purity, and inconsistent batch potency. Ensuring reproducible cargo loading and stable retention of bioactivity during storage and transport also remains challenging. In addition, exosomes carry endogenous biomolecules whose immunological effects and safety profiles require stringent quality control.59 Emerging solutions such as microfluidic purification, tangential-flow filtration, scalable cell-factory systems, synthetic exosome platforms, and defined-release assays aim to address these issues. However, regulatory clarity and robust manufacturing standards are still required before exosome-based nanotherapies achieve widespread clinical adoption.60

Plant Exosome-like Nanovesicles (ELNVs) which can be pre-potentiated by edible plants (eg ginger) have also shown promise and have been tested in their potential to alter the TME or failing to deliver chemotherapeutics with minimal side effects.61 The latest research includes “designer exosomes” engineered either after isolation or being biosynthetically produced using genetically modified donor cells to achieve tailored therapeutic functions. An example is using tumor-derived exosomes to encapsulate doxorubicin or paclitaxel and to target triple-negative breast cancer through active targeting (surface-engineering) in exosomes (EGFR antibodies). One of the most potential technological breakthroughs is the so-called hybrid exosome system in which natural exosomes are temporarily bound with synthetic liposomes or polymeric NPs to essentially harness the biocompatibility of the natural vesicles and the practical adaptability of the engineered nanocarriers.62 In some preclinical studies, such hybrids have shown increased circulation time, more evasion of the immune system, and increased drug payload. However, EVs and exosomes have major issues regarding clinical translation, such as difficulty in high-scale isolation, consistency of cargo loading or batch-to-batch consistency. As a solution to this, microfluidics and tangential flow filtration scale-up technologies are under development that will be able to scale to clinical-grade products under GMPs.63 Further, exosome mimetics, nanovesicles artificially secreted by cell membranes and having a higher yield than natural exosomes are being studied, although with similar targeting abilities. Taken together, exosomes are a natural example of nature-inspired nanocarriers that can address top challenges related to cancer therapy immune evasion to crossing biological barriers facilitating next-generation immunotherapy, gene editing, and adaptive combination regimens. First-in-human studies, such as ExoSTING (NCT04592484), are crucial to support the validation of exosomes as living smart nanocarriers to support precision oncology.64

Hybrid and Multifunctional Nanocarriers

Hybrid nanocarriers combine organic and inorganic components or multiple organic matrices to integrate targeting, imaging, and therapeutic functions; however, this multifunctionality comes with structural design trade-offs. Increased architectural complexity can influence colloidal stability, surface integrity, and degradation kinetics, potentially affecting release profiles.65 Rigid inorganic cores may enhance stability but slow biodegradation, whereas fully organic hybrids may degrade rapidly and compromise mechanical robustness.66 Current design strategies address this by using modular core-shell architectures, cleavable inorganic–organic linkers, degradable polymer shells, and stimuli-responsive shedding layers to ensure timely disassembly.65 Complementary approaches, such as design-of-experiments-guided optimization, microfluidic synthesis, and biodegradation-rate tuning, allow hybrid systems to balance stability, biodegradability, and control release while retaining clinical feasibility.67

Hybrid and multi-functional nanocarriers are the best of nano-oncology in the modern era in that they synthesize the properties of several materials or design principles into one smart platform that can address the multidimensional nature of cancer. These systems, through the combination of organic, inorganic, and biomimetic components, are capable of delivering, sensing, responding, and adapting at the same time and thus fulfilling the need between specific delivery and real-time theranostics.68 The most prominent ones are lipid polymer hybrid NPs (LPNPs), combining the biocompatibility as well as the long circulation times of liposomes with structure stability and controlled release of polymeric cores.69 LPNPs have demonstrated greater encapsulation efficiency of both hydrophilic as well as hydrophobic drug molecules. One has been the derivation of hybrid systems whereby Genexol-PM (polymeric micelle for paclitaxel; NCT01249293) is derived of micelles assembled with a liposomal shell in a way such that tumor retention is enhanced whilst limiting burst release.70 Another popular design is core-shell NPs. The more usual ones involve a core composed of a polymer or an inorganic material loaded with the drug, with a lipid or PEGylated shell giving stealth and active targeting.70 Examples are gold-liposome hybrids where the photothermal functionality of gold nanoshells and a drug delivery capability of liposomes freely combine to, in this case, exploit heating-activated drug release along with simultaneous imaging. This kind of material has been studied in early clinical trials for recurrent head and neck tumors. Multistage hybrid nanocarriers made in response to sequential tumor barriers represent a frontier innovation. As an example, a NP may first escape detection by immune systems via PEG and afterwards, release its stealth outer surface in the acidic TME to reveal a cell-penetrating peptide to penetrate deep tumors. In vitro models of PLGA cores, lipid layers, and pH-labile linkers have shown enhanced infiltration of hypoxic tumor areas.71 Another emerging family of hybrids iinclude metal-organic frameworks (MOFs) due to their high porosity, pore size that can be tailored, and high payload load capacity, such as proteins and genes.

Current MOF applications include the co-delivery of chemotherapeutics and siRNA or in the production of reactive oxygen species using nanocatalysts to increase tumor killing. There are preliminary studies that combine MOFs with targeting ligands or biomimetic coatings to highlight their potential as the next-generation of adaptive nanomedicine. A promising new route is that of the composite natural/synthetic module, eg, exosome-hybrid-polymer.72 They take advantage of the natural homing and biocompatibility of the exosomes and increase drug loading ability and structural factor with synthetic polymer cores. This hybridization is especially promising in crossing obstacles beyond current capabilities, such as the BBB in glioblastoma treatment, an area of fast preclinical development.73 To even promote multifunctionality further, they are incorporating actual-time diagnostic modules in the hybrid carriers. An example would be contrasting MRI or fluorescence probes co-delivered with therapeutics so clinicians can see not only where and how parts are spreading, but also drug release and response in time, ie a first step towards precision and adaptive dosing in the clinic. Anyhow, multifunctional hybrids are still hard to translate. Scale up, replication of batches, and regulatory approval may be a problem with complicated architectures. Artificial intelligence and high-throughput microfluidic fabrication methods to generate the most efficient hybrid formulation and manufacturing pipelines are emerging techniques to produce the most viable production pipelines.

Altogether, hybrid and multifunctional nanocarriers are the future of smart nanomedicine against cancer - multi-layered, multi-stimuli, multi-modal platforms implemented to outsmart tumor heterogeneities, resistance, and fluctuating micro-environments. In their approach, which includes therapy, imaging, and smart response into the same construct, they reconceptualize how cancer will be treated in the future by clinicians in real time.74

Real-Time Monitoring and Modeling of NP–TME Interactions

To better capture the dynamic nature of the tumor microenvironment, emerging experimental and computational platforms are enabling real-time visualization and prediction of hybrid nanoparticle behavior in vivo. Intravital multiphoton and light-sheet microscopy permit high-resolution monitoring of nanoparticle trafficking, vascular extravasation, and stromal penetration.75 Complementary non-invasive methods such as PET/MRI, photoacoustic imaging, Raman spectroscopy, and FRET-based nanosensors provide longitudinal insight into biodistribution, release kinetics, and TME biochemical changes. On the computational front, agent-based modelling, multiscale pharmacokinetic-pharmacodynamic simulations, spatial systems biology, and AI-driven digital-twin tumor models are increasingly being used to forecast nanoparticle transport, immune modulation, and adaptive TME responses.76 These integrative tools support the rational design and optimization of hybrid nanocarriers by predicting performance in heterogeneous and evolving tumor niches, accelerating the translation of precision nanomedicine.77 An overview comparison is provided in Table 1.

Table 1 Verified Comparison of Nanocarriers in Oncology

Tumor Targeting Strategies Using Nanotechnology

To address tumor heterogeneity, nanocarriers are increasingly engineered with multi-ligand surfaces (eg, dual targeting of integrins and EGFR), enabling recognition of diverse tumor cell subpopulations. Stimuli-responsive platforms tuned to the tumor microenvironment (pH, enzymes, hypoxia, etc.) allow for adaptive drug release across variable intratumoral niches.84 Biomimetic coatings (platelet, cancer-cell, or macrophage membranes) enhance immune evasion and broad tumor tropism, improving intratumoral penetration despite phenotypic variability.85 Integration of real-time imaging with nanotheranostics also supports adaptive treatment planning for evolving tumor profiles.86 These interactions are shown schematically in Figure 1.

Figure 1 Schematic representation of the dynamic interaction pathways between engineered nanocarriers and the TME. Illustrated steps include: (1) Systemic circulation of nanocarriers, (2) Vascular extravasation via EPR, (3) Ligand-mediated active targeting of tumor-specific receptors, (4) Deep tumor penetration, (5) Navigation and diffusion through the dense extracellular matrix (ECM), (6) Receptor-mediated endocytosis and cellular internalization, (7) Stimuli-responsive drug release triggered by tumor-specific cues (eg, pH, enzymes, redox), (8) Modulation of immune components within the TME to overcome immunosuppression, and (9) Final therapeutic action for maximal antitumor efficacy.

Passive Targeting and the Enhanced Permeability and Retention (EPR) Effect

Although EPR is an essential concept of tumor nanomedicine, its clinical application has been limited by considerable inter-patient variation and heterogeneity across tumor types. In an attempted revival of the passive delivery approach, most current investigations are swinging to TME priming, a mix of nanomedicines and stroma-corrective medicines that restore the contracted extracellular matrix and shrink tumor blood vessels.87 As a case in point, co-administration with losartan, an angiotensin receptor blocker, has been found promising in blood vessel decompression and NP penetration in desmoplastic malignancies such as pancreatic ductal adenocarcinoma, where Phase 1 data (NCT01821729) shows that perfusion of drugs is enhanced. There are also complementary methods: interstitial transport is additionally increased by enzyme degradation of hyaluronic acid (eg, PEGPH20) and low-dose metronomic chemotherapy.88 In addition to pharmacological preconditioning, patient stratification with advanced image-guided approaches is being developed with the potential to process the most effective patient stratification based on the dynamic contrast-enhanced MRI to detect patients with an already high EPR potential. On-demand delivery can also be achieved with physical methods (such as focused ultrasound and microbubble cavitation), temporarily rupturing tumor vasculature in order to enhance NP extravasation. All of these innovations represent a paradigm shift: rather than giving up on EPR, next-generation training to the TME can enable passive targeting to occur reliably in the clinic.89

While the EPR effect remains an important mechanistic foundation in nanomedicine, increasing clinical evidence confirms that its magnitude is highly variable among patients and tumor types due to vascular heterogeneity, stromal density, and immune pressure within the tumor microenvironment.90 Consequently, passive targeting alone may not guarantee sufficient therapeutic delivery in all clinical settings.91 Emerging approaches including ligand‐decorated active targeting systems, biomimetic nanoparticles (eg, cell membrane–coated carriers), and immune system or cell-mediated delivery (eg, macrophage- and MSC-based vectors) are being developed to complement or bypass EPR dependency. Together, these strategies provide more consistent tumor localization and represent a rational evolution toward hybrid targeting designs in clinical nano-oncology.87

Active Targeting, Ligand Engineering for Multi-Target and Immuno-Smart Nanocarriers

Active targeting has progressed well beyond the traditional ligand labeling with folate or transferrin. The potential of the current frontier entails multi-specific nanocarriers designed to target simultaneously multiple tumor hallmarks. As another instance, NPs with two ligands (ie, RGD peptides (integrins) and VEGFR2 antibodies) have been reported to show synergy when targeting tumors (both cancer cells and vasculature) and are beneficial in targeting heterogeneous tumors by enhancing payload delivery and retention. Immune checkpoint targeting is also being incorporated onto NP surfaces with cutting edge designs.92,93 One of the most promising trends in 2024–2025 was the synthesis of anti-PD-L1-functionalized nanogels that would deliver siRNA or CRISPR components to a tumor and also target the local tyrosine kinase pathway immunosuppressive components, making the tumor-associated macrophages change their phenotype from M2 to the tumoricidal M1.94 The given combinatorial targeting strategy increases specificity, reduces the risk of off-target effects, and resorts to the counteraction of tumor immune evasion decipherly. Furthermore, ligand clustering using multivalent ligands and DNA origami nanoarchitecture are providing the ability to tune ligand density and possess higher avidity with or without loss of stealth. These developments are indicative of an important shift: next-generation active targeting no longer will only serve as a delivery mechanism, but a multi-dimensional, immune-integrated precision-based strategy designed to overcome tumor adaptability.95

Stimuli-Responsive Systems, Logic-Gated Smart Release

Patients and clinical researchers have seen a rapid development in stimuli-responsive nanocarriers in the gradual progress of complex release governed by logic-gates having multi-stimuli control.96 Differential TME signals such as acidic pH, redox gradients, enzyme overexpression, or localized hyperthermia, are also used by these inputs to elicit immediate payload delivery (Figure 1). Some more recent concepts use AND-gate creation, with payloads only being activated in the presence of two or more activators, which greatly minimizes off-target leakage.97 As an example, pH-sensitive linkers and disulfide-bonded hybrids were functionalized on microtomes to be inert in circulation and disintegrate within tumors strongly presented with low-pH and glutathione, in order to guarantee the release of payloads at the appropriate site.98 Temperature-sensitive liposomal doxorubicin, ThermoDox 120microg/mL, showed the prospect of externally activated release in combination with radiofrequency ablation; however, as evidenced in its Phase III results (NCT02181075), thermal-dose specificity was required to achieve success. Innovative ideas in 2025 include nanogels activated by enzymes to break down selectively in tumor-overexpressed matrix metalloproteinases and NPs that can amplify the generation of ROS to enhance chemotherapeutic effects by chemical synergy. The next step is to combine several stimuli-responsive triggers, logic gate and real-time imaging, and this will turn stimuli-responsive systems into intelligent theranostic machines to eradicate the dynamic tumor.99

The physicochemical properties of nanocarriers strongly influence biodistribution and clearance. In general, particles sized ~50–120 nm with near-neutral or zwitterionic surfaces and hydrophilic coatings, such as dense PEG or POx layers, demonstrate prolonged circulation and reduced opsonization, whereas particles <6–8 nm undergo rapid renal clearance and positively charged surfaces are prone to protein adsorption and hepatic uptake.100 These mechanistic factors guide tumor delivery, protein corona interactions, immune recognition, and RES sequestration across platforms including liposomes, polymeric nanoparticles, inorganic systems, and extracellular vesicles.101 Meanwhile, advanced stimuli-responsive and logic-gated nanocarriers are being engineered to discriminate tumor tissue from healthy environments by responding to combinations of cues such as mildly acidic pH, elevated glutathione, hypoxia, or tumor-associated enzymes. Rather than relying on a single trigger, modern systems frequently use AND-logic (eg, pH AND redox) to ensure payload activation only under tumor-specific microenvironmental thresholds, thereby reducing false activation in inflamed or physiologically stressed tissues.102 Safety-interlock strategies, ratiometric sensing, and validated trigger windows help maintain selectivity amid physiological fluctuations, supporting more reliable differentiation between malignant and healthy tissues.103 Collectively, the rational tuning of particle size, charge, hydrophilicity, and logic-gated responsiveness enhances precision delivery and improves translational robustness in diverse tumor settings.104

Cell-Mediated Delivery, Living Taxis for Deep Tumor Penetration

Immune and stem cell-based nanoparticle delivery platforms show strong potential for targeted transport and deep tumor penetration; biosafety considerations are essential for clinical translation. Immune-cell carriers may trigger unintended immune activation or cytokine release if over-stimulated.105 In contrast, stem-cell-based carriers carry a theoretical risk of ectopic engraftment or tumorigenic transformation if proliferative capacity is not carefully controlled.106 To address these concerns, emerging strategies include pre-irradiation or genetic modification to limit cell division, use of apoptotic-switch circuits or drug-inducible kill switches, and thorough ex vivo quality control to ensure immunological compatibility and phenotypic stability. Continued refinement of cell engineering and safety screening is expected further to support the clinical development of living-cell-based nanoparticle delivery systems.107 One of the most revolutionary future tools in nanomedicine is the emergence of cell-based delivery, which would use living cells as a biological carrier to transport NPs past biological obstacles to directly go into the depths of the tumor.

Hitchhiking NPs (such as macrophage-hitchhiking NPs) take advantage of the natural tropism of macrophages to immunologically privileged hypoxic tumor sites.108 Glioblastoma and triple-negative breast cancer preclinical tumor models have demonstrated that macrophages loaded ex vivo with iron oxide or polymeric NPs may migrate into the tumor core past the thick tissue unit. This concept is being actively translated into early-phase clinical research studies such as the City of Hope “The Trojan Horse” cell delivery program. Similarly, nanotherapies with mesenchymal stem cells (MSC) is rising to breach the BBB and reach metastatic niches; GMP grade procedures are now being piloted in Asia in the case of glioma.109 There is also the area of engineered T-cell ferries where T-cells with chimeric antigen receptor (CAR)-T allow deliveries of two-pronged therapies with multiple functions directly into the TME, keeping the cytotoxic T-cell activity intact through attaching NP-based payloads (such as immunostimulatory nanogels or cytokine microcapsules). Cell therapy and nanomaterials represent a living nano-factory with a level of tumor penetration, accuracy, and modulation of immune cells, unequaled in otherwise untreatable cancers.110

Therapeutic Applications Chemotherapy: Overcoming Multidrug Resistance

Conventional chemotherapy has been limited by the inability to selectively target tumors, toxicity to the whole body and induced MDR through efflux mechanisms such as P-glycoprotein. Nanotechnology is changing this paradigm by introducing smart drug delivery systems that overcome efflux mechanisms, co-deliver chemosensitizers and deliver locally. An example is polymeric micelles co-loaded with paclitaxel and P-glycoprotein inhibitors (including tariquidar) which exhibit impressive tumor retention in MDR models.111 Liposomal doxorubicin (Doxil) is still a landmark; however, more recent stimuli-responsive nano carriers such as pH/redox-sensitive dendrimer-drug conjugates show greater penetration into resistant tumor cores, and release cargoes in a controlled manner among acidic intracellular environments. Markedly, exosome-mimetic NPs constructed from patient cells are in Phase I discovery toward personalized chemo based on patient intrinsic immune system evasion overcoming MDR.112

Radiotherapy: Radiosensitizers

NPs have the ability to become strong generators of radiosensitizers by enhancing local radiation dose deposition and surpassing radioresistance. High-Z NPs are inorganic typically employed in cancer (AuNPs and NBTXR3; Phase III trial NCT04862455) by increasing the photoelectric effect in the tumor, thereby increasing DNA damage. Also, iron oxide NPs that target tumors are under investigation as potential combined hyperthermia-radiosensitizing agents.113 Other potential applications of multifunctional nanoplatforms are the co-delivery of DNA repair inhibitors (such as PARP inhibitors) with metal-based NPs to deliver synergistic effects on both radiosensitization and minimize normal tissue exposure. Trending materials are shape- and size-optimized gold nanorods and biodegradable cerium oxide NPs that scavenge reactive oxygen species in healthy tissues and increase oxidative stress within tumors.114

Photothermal and Photodynamic Therapy

Photothermal therapy (PTT) and photodynamic therapy (PDT) utilize light energy as a spatially selective cancer ablative modality. Nanotechnology takes these modalities a step higher by increasing tumor delivery of therapeutic agents (photothermal materials: Au NPs, CNTs) and photosensitizers (porphyrin-containing liposomes), as well as enhancing the delivery of other therapeutic agents (porphyrin-loaded liposomes).115 Irrespective of whether they convert light to heat (NIR) (as a potent inducer of apoptosis) or generate ROS, at near-infrared (NIR) irradiation, such nanoplatforms are confined to induce apoptosis.116 New developments of theranostic NPs are merging imaging features with PTT/PDT which allows for real time-monitoring. Recovery is new in the form of organic-inorganic hybrid nanogels characterized by dual mode photothermal/photodynamic behavior and exosome-coated graphene quantum dots, providing deep tissue penetration and low-off target damage.117

Nanocarrier Strategies to Modulate PD-1/PD-L1 and CTLA-4 Signaling

Rational nanocarrier design enables spatially and temporally controlled checkpoint modulation to better reverse tumor immune evasion. First, lymph-node–addressed carriers (eg, ~10–50 nm, albumin-hitchhiking or chemokine-decorated) can deliver anti-PD-1/anti-CTLA-4, agonists of co-stimulatory axes (CD40/OX40/4-1BB), or mRNA/siRNA that tune T-cell priming while limiting systemic exposure.118 Second, TME-restricted release via pH/redox/enzyme-responsive shells or photo/ultrasound triggers localize checkpoint blockades and dose-spares to reduce immune-related adverse events. Third, gene-level modulation of PD-L1 on tumor or myeloid cells (siRNA/ASO/CRISPR or miR-34a/miR-200 restoration) downshifts inhibitory signaling upstream of the receptor–ligand interaction.119 Fourth, combo nanotherapies co-deliver checkpoint agents with STING/TLR agonists, cytokines (eg, IL-12), or TAM-reprogramming cargos (CSF1R/PI3Kγ inhibitors) to convert “cold” TMEs to inflamed, checkpoint-responsive states.120 Fifth, logic-gated designs (eg, AND-gates requiring acidic pH and high GSH) and decoy/trap nanoparticles that sequester PD-L1 in the TME further increase on-target specificity. Together, these approaches enhance antigen presentation and effector T-cell function, mitigate systemic toxicity, and provide a tunable framework for synergizing PD-1/PD-L1 and CTLA-4 pathway intervention.121

Immunotherapy: Nanovaccines, mRNA Delivery, and Adjuvants

Nanocarriers (NCs) are transforming cancer immunotherapy by targeting dendritic cells and lymph nodes with the delivery of tumor antigens, immunostimulatory adjuvants or mRNA-based vaccines. The most modern nanovaccines at the clinical-level use lipid NPs (LNPs) to deliver mRNA payload encoding tumor neoantigen-specific vaccines, with success in patients confirmed by the personalized cancer mRNA vaccine platform of BioNTech (eg, BNT122, Phase II NCT03815058).122 Co-loading of STING agonists with checkpoint inhibitors in polymeric NPs has shown augmentation of T-cell activation and infiltration of the TME in malignant melanoma. Additionally, nanoadjuvants are under development based on dendrimers in order to cross-present antigens and re-educate immunosuppressive cancer-associated macrophages (TAMs) to an M1 phenotype in order to enhance the checkpoint blockade immunotherapy response.123

Gene Therapy: SiRNA and CRISPR/Cas9

Genome editing and gene silencing have massive potential for the correction of oncogenic drivers. The prominent barrier of naked nucleic acid instability and off-target delivery is surmounted through the use of NPs.124 Clinical validation of mRNA and siRNA options is demonstrated by the use of lipid NPs, and new-generation polymer and exosomal nanocarries have been tailored for exact gene knockdown and editing. The siRNA therapies developed by Alnylam thus opened up siRNA BCL2, KRAS, or MYC-focused anti-cancer siRNANO-based pipelines. At the same time, CRISPR/Cas9-loaded gold nanoclusters and lipid-based nano-formulations are accelerating towards clinical-grade GMP scale-up with first-in-human trials expected within the next 2–3 years.125

Combination Therapies: Multimodal Synergy

Complex and adaptive tumors are becoming resistant to single-modality therapy. Nano vehicles enhance the spatiotemporal concomitant use of chemo-, radio-, immuno-, and gene therapy, allowing one to harness strong synergistic effects into one platform. Specifically, siRNA to silence MDR genes is co-encapsulated with liposomes to show dramatic tumor regression under pre-clinical breast cancer conditions. Photosensitizers-plus-checkpoint inhibitor nanogels make it possible for both PTT/PDT and immune stimulation to be combined in a single treatment. Smart hybrid nanosystems combine image-guided delivery, logic-gated release and enhanced targeting, and established nanomedicine as the foundation for the next generation of combination oncology.126,127 Some approved and pipeline nanotechnology-based therapies are summarized in