Advances in Cancer Treatment Through Nanotheranostics and Emerging Therapies

Abstract

The integration of nanotheranostics into cancer treatment represents a transformative shift in oncology, combining precision diagnostics with targeted therapeutic interventions. This manuscript explores the advancements in nanotechnology-driven cancer therapies, highlighting the role of engineered nanoparticles, such as liposomes, dendrimers, polymeric micelles, and virus-like particles, in enhancing drug delivery, real-time imaging, and tumor-specific targeting. Additionally, emerging therapies, including immunotherapy, gene editing, and chromophore-assisted light inactivation (CALI), are discussed in the context of personalized medicine. The convergence of these strategies is poised to redefine cancer treatment paradigms, improving therapeutic efficacy while minimizing systemic toxicity. This review outlines the key challenges, current limitations, and future directions in nanotheranostic applications, emphasizing the need for interdisciplinary collaboration to optimize their clinical translation.

1. Introduction

Cancer treatment has undergone a profound transformation with the emergence of nanotheranostics [1] and other innovative therapies [2,3,4]. These advancements have enabled personalized, highly precise interventions that have significantly improved therapeutic outcomes. Researchers have emphasized the utility of nanomaterial-based agents, such as graphene and lipid nanoparticles, which facilitate targeted diagnosis and efficient treatment delivery, minimizing systemic toxicity and optimizing therapeutic responses [5].

The field of nanotheranostic integrates diagnostic and therapeutic modalities at the nanoscale, revolutionizing cancer detection, monitoring, and treatment strategies. Engineered nanoparticles are designed to deliver therapeutic agents selectively to tumor cells whilst simultaneously enabling real-time imaging and treatment monitoring. This dual functionality reduces the off-target effects and enhances precision, paving the way for adaptive and personalized treatment strategies [6,7,8].

Nanoparticles, including liposomes, dendrimers, aptamers, and other organic/inorganic nanocarriers, are widely employed for chemotherapeutic drug delivery, gene transfer, and immunotherapeutic applications (Figure 1). These nanocarriers can be functionalized with targeting ligands, such as antibodies or peptides, facilitating high specificity toward tumor-associated markers and sparing healthy tissues [9,10,11,12]. Additionally, many nanoparticles respond to tumor-specific stimuli, such as pH, temperature, or enzymatic activity, ensuring controlled drug release for enhanced efficacy [9,10,11,12].

Beyond drug delivery, nanotheranostic platforms provide high-resolution imaging capabilities, utilizing modalities such as fluorescence, magnetic resonance imaging (MRI), and computed tomography (CT), enabling precise tumor localization and treatment tracking [13,14].

1.1. Overview of Cancer Treatment Challenges

Cancer treatment presents multifaceted challenges, spanning biological complexity, diagnostic hurdles, treatment resistance, economic constraints, and psychosocial impact [15,16,17]. A major obstacle is the heterogeneity and plasticity of cancer cells [18,19,20], which necessitates individualized therapeutic approaches. Cancer is not a singular disease, but comprises diverse types and subtypes, each with unique genetic and molecular characteristics. This variability complicates efforts to establish universal treatment protocols and necessitates targeted therapy strategies, which vary in their efficacy across patient populations [21,22]. Furthermore, tumor adaptability fosters resistance to traditional treatments, such as chemotherapy and radiation, undermining long-term disease control [23,24].

Early detection remains a critical challenge, as many cancers exhibit asymptomatic progression in their initial stages, leading to late-stage diagnoses that complicate interventions [25,26]. Additionally, unequal access to diagnostic technologies in low-resource settings further exacerbates the disparities in patient outcomes [27,28].

Treatment-associated toxicity is another pressing concern, with chemotherapy, radiation, and targeted therapies often inducing immune suppression, fatigue, and organ damage, diminishing quality of life and treatment adherence [29,30]. Furthermore, financial constraints pose additional barriers, as cutting-edge cancer therapies are frequently cost-prohibitive for patients and healthcare systems alike [31,32]. Addressing these limitations requires interdisciplinary collaboration to enhance treatment accessibility, affordability, and patient-centered care.

1.2. Nanotheranostics as a Promising Approach

Nanotheranostics represents a cutting-edge biomedical strategy that integrates diagnostic and therapeutic functions within a single nanoparticle-based platform [33,34]. Engineered nanomaterials, such as liposomes, polymeric nanoparticles, quantum dots, gold nanoparticles, and magnetic nanoparticles, are designed to deliver imaging agents, therapeutic payloads, and targeting ligands for selective tumor localization and drug administration [35,36,37,38].

This technology enables real-time monitoring of treatment responses, enhances drug targeting, and reduces systemic toxicity through biomarker-guided delivery and stimuli-responsive release mechanisms, triggered by tumor-specific factors, such as pH, enzymatic activity, or hypoxia [39,40,41,42]. Applications span multimodal imaging (MRI, CT, and fluorescence) and tailored interventions suited for personalized oncology [43,44,45,46].

Despite significant progress, nanotheranostics faces challenges in terms of biocompatibility, large-scale manufacturing, and regulatory approval. Nonetheless, innovations in material science and bioengineering continue to push these platforms toward routine clinical integration [45,46].

Building on these technological strides, the integration of nanotheranostics with immuno-oncology offers a compelling frontier for precision cancer therapy. Recent studies have illuminated the molecular and immunological underpinnings that govern therapeutic response, particularly in the context of immune checkpoint blockade. For instance, targeted next-generation sequencing has revealed specific genomic markers predictive of PD-1 inhibitor efficacy, underscoring the value of molecular profiling in patient stratification [47]. Tumor mutational burden (TMB) has emerged as a robust biomarker, with higher TMB correlating with improved responses to immunotherapy, likely due to increased neoantigen presentation and immune recognition [48,49].

Beyond genetic predictors, the tumor microenvironment and its interplay with the immune system play a pivotal role in modulating treatment outcomes. Genomic determinants have also been linked to radiation therapy responsiveness, suggesting that integrated approaches combining nanotheranostics with radiotherapy could enhance immunogenic cell death and therapeutic synergy [50]. The immune system’s dual role in tumor suppression and progression further complicates treatment paradigms yet offers opportunities for targeted modulation [51]. The cancer-immunity cycle, as conceptualized by Chen and Mellman, provides a framework for understanding how therapeutic interventions can amplify antitumor immunity at multiple stages [52].

T cell-based strategies continue to gain traction, with translational research highlighting their clinical relevance and potential for durable responses [53]. PD-1 blockade, for example, has been shown to reverse adaptive immune resistance, reinvigorating exhausted T cells and promoting tumor regression [54]. Combination therapies, such as nivolumab plus ipilimumab, have demonstrated enhanced efficacy in advanced melanoma, albeit with increased toxicity, reinforcing the need for precision-guided regimens [55]. Moreover, PD-L1 expression remains a key predictive biomarker, guiding treatment selection and informing prognosis [56].

Together, these findings underscore the importance of integrating molecular diagnostics, immune profiling, and nanotechnology to tailor cancer therapies. As nanotheranostics evolves, its convergence with immunotherapy promises to unlock new dimensions of personalized medicine, transforming cancer care through synergistic, biomarker-driven interventions.

2. Nanotechnology-Driven Cancer Solutions

2.1. Significance of Nanotheranostics

Clinically, nanotheranostics supports dynamic treatment monitoring and individualized therapy adjustment, especially critical in heterogeneous cancers with variable treatment responses [57,58]. Through targeted payload delivery and real-time imaging, these systems improve intervention timing and reduce adverse effects [59,60,61,62].

By customizing nanoparticle formulations to match tumor-specific molecular profiles, nanotheranostics enhance therapeutic accuracy and minimizes resistance [63,64]. These benefits extend beyond oncology to fields including cardiology, neurology, and infectious disease diagnostics [65,66,67,68].

2.2. Role of Nanoparticles in Enhancing Treatment Efficacy

Nanoparticles offer unique advantages in cancer therapy due to their high surface-area-to-volume ratio, tunable chemical properties, and ability to penetrate biological barriers [69,70,71]. Functionalized nanoparticles target tumor biomarkers with high selectivity, improving drug accumulation in malignant tissues while sparing healthy cells [72,73,74].

Advanced designs enable controlled drug release, maintaining therapeutic levels over time and minimizing systemic toxicity [75,76]. Metallic nanoparticles, such as gold and iron oxide, also serve as imaging contrast agents, improving tumor visualization via MRI and CT [77].

These innovative applications include photothermal therapy, where gold nanoparticles generate localized heat for tumor ablation [78,79], and gene delivery systems for transporting siRNA or CRISPR/Cas9 complexes to modulate oncogenic pathways [80,81]. As the research advances, nanoparticle-based modalities will continue to redefine the standards for cancer treatment efficacy and personalization [82].

3. Nanotechnology-Enabled Detection of Circulating Tumor Cells and Cancer Biomarkers

The detection and analysis of circulating tumor cells (CTCs) and cancer biomarkers (CBs) have emerged as pivotal components of precision oncology, offering real-time insights into tumor behavior, therapeutic responsiveness, and disease progression [83,84]. Leveraging nanotechnology, these indicators can now be captured and profiled with enhanced sensitivity and specificity, transforming early diagnosis and individualized treatment strategies.

CTCs are malignant cells shed from primary tumors into the bloodstream, serving as key mediators of metastasis [85,86]. Their molecular characterization reveals oncogenic mutations, resistance markers, and tumor heterogeneity—information critical for refining therapeutic decisions [87,88,89,90]. Nanotechnology facilitates their isolation via high-resolution microfluidic platforms and immunomagnetic separation techniques that exploit nanoscale functionalization to enhance detection sensitivity [91,92].

Cancer biomarkers, including proteins, DNA fragments, and metabolites, further complement liquid biopsy diagnostics by identifying the disease stage, predicting treatment outcomes, and guiding drug selection [93,94]. Nanoparticle-enabled biosensors and assay platforms have significantly improved biomarker recognition, enabling detection of key indicators, such as HER2 [95], PSA [96], and EGFR mutations [97], with increased precision.

The integration of nanotechnology into CTC and biomarker profiling has fostered non-invasive, real-time patient monitoring [98,99]. These systems amplify trace signals, reduce background interference, and facilitate multiplexed detection, streamlining cancer diagnostics across various tumor types.

3.1. Nanoscale Strategies for CTC Isolation and Monitoring

Nanotechnology enhances CTC detection by enabling highly sensitive liquid biopsy platforms that provide dynamic snapshots of tumor biology [100,101]. Unlike conventional imaging and biopsies, nanoscale filtration and antibody-coated magnetic nanoparticles can selectively isolate CTCs, supporting early detection and longitudinal monitoring [102].

CTC enumeration and profiling allow clinicians to track therapeutic effectiveness— declining counts signal treatment success, while increasing levels may reflect disease progression [103,104,105,106]. Nanostructured surfaces and molecular recognition elements also improve the capture efficiency, supporting downstream analyses of drug resistance mechanisms and metastatic potential [107,108,109,110]. Nevertheless, challenges such as CTC rarity and technological standardization persist, hampering further innovation in nanofluidic design and particle engineering [111,112].

3.2. Nanotechnology in Cancer Biomarker-Driven Therapy

Cancer biomarkers, when integrated with nanotechnology, enable personalized treatment strategies that target specific genetic and molecular abnormalities [113,114,115]. Nanocarriers conjugated with antibodies or aptamers selectively bind to biomarker-expressing cells, facilitating localized delivery of therapeutic agents and imaging probes [116,117].

For HER2-positive breast cancer, nanosystems delivering trastuzumab can enhance therapeutic precision [118,119]. Similarly, targeted nanoparticles can deliver TKIs to EGFR-mutant lung cancer cells, mitigating off-target effects [120,121]. Nanotechnology also plays a role in immunotherapy monitoring. Biosensors can detect PD-L1 expression, MSI, and TMB with high accuracy, informing checkpoint inhibitor eligibility and immune response profiling [122,123,124,125,126].

Advanced nanoparticle platforms further enable real-time tracking of circulating tumor DNA (ctDNA), empowering clinicians to adapt treatment plans dynamically [127,128,129,130]. Despite the current limitations regarding detection variability and cost, the ongoing developments in nanoproteomics and genomics are refining biomarker-guided interventions for optimal patient outcomes [131,132].

4. Integration of Cancer Treatment with Conventional Therapies

The integration of emerging cancer therapies with conventional treatments is reshaping oncology by combining innovation with established methodologies [133]. Traditional approaches, including surgery, chemotherapy, and radiotherapy, have long been the cornerstone of cancer care, offering proven efficacy for tumor reduction [134]. However, these techniques often pose challenges, including toxicity, resistance mechanisms, and treatment limitations [135]. Recent studies that exemplify this evolving landscape include the following:

• Nanocarrier-Assisted Drug Delivery in Immunotherapy: presented programmable nanocarriers that synergize with checkpoint blockades, improving selective tumor targeting and reducing systemic toxicity [136].
• Bioresponsive Platforms for Oral Peptide Delivery: introduced pH-sensitive nanoarchitectures that protect therapeutic peptides during gastrointestinal transit, offering a non-invasive alternative to injectable regimens and complementing traditional modalities [137].

By combining novel treatments, such as immunotherapy, gene editing, and targeted therapies, the medical field is enhancing precision and reducing toxicity [138]. Immunotherapy, through immune checkpoint inhibitors and CAR-T cell therapy, provides synergistic benefits when paired with conventional approaches [139]. For example, radiotherapy can enhance immune activation, making immunotherapeutic agents more effective [140].

Targeted therapies, including tyrosine kinase inhibitors (TKIs) and monoclonal antibodies, offer molecular-level precision, minimizing damage to healthy cells whilst improving tumor specificity [141,142]. Additionally, the fusion of chemotherapy and nanomedicine-based drug delivery systems optimizes treatment efficacy by reducing systemic toxicity [143].

Precision medicine further refines personalized treatment strategies, ensuring that therapies align with an individual’s tumor genetics and biomarker profile [144,145]. Notably, mutations such as BRCA1 in breast cancer or EGFR in lung cancer can guide specific treatment protocols, enhancing the therapeutic outcomes [146].

Despite its promise, integrated cancer treatment faces challenges, including clinical validation of combined approaches, multidisciplinary coordination, and financial constraints [147]. Continued research and policy adjustments are essential to ensuring broader access to advanced treatment combinations, ultimately improving long-term patient survival and quality of life [148].

4.1. Enhancement of Radiotherapy Through Nanotechnology

The integration of nanotechnology into radiotherapy has significantly improved cancer treatment by enabling precise tumor targeting, increasing therapeutic efficacy, and minimizing damage to surrounding healthy tissues [149]. Despite its effectiveness, radiotherapy poses challenges, such as radiation resistance, toxicity, and off-target effects, which nanotechnology helps address [150].

One key advancement is the development of radiosensitizers, which are nanoparticles designed to amplify radiation-induced damage in cancer cells [151]. Gold nanoparticles, for instance, have shown remarkable radiotherapy enhancement due to their high atomic number, which increases X-ray absorption and secondary electron generation, thereby intensifying tumor destruction while sparing adjacent tissues [152,153]. Similarly, hafnium oxide nanoparticles have demonstrated comparable radiosensitizing effects, thereby widening their clinical potential [154].

Nanotechnology also improves therapeutic agent delivery in combination with radiotherapy. Nanoparticles facilitate tumor-specific targeting, ensuring that radiation-enhancing agents accumulate preferentially within cancer cells, thereby improving efficacy whilst minimizing systemic toxicity [155].

Additionally, theranostic nanoparticles (which combine imaging and therapeutic functions) offer real-time tumor visualization, aiding in precise treatment adjustments [156,157]. Imaging agents, such as gadolinium and iron oxide nanoparticles, enhance MRI and CT scans, enabling accurate tumor localization and monitoring [158].

Another critical challenge in radiotherapy is tumor hypoxia, where oxygen-deficient regions exhibit radiation resistance [159]. Nanotechnology addresses this issue by introducing oxygen-carrying nanoparticles or reactive oxygen species (ROS)-generating nanoparticles, which reoxygenate the hypoxic tumor areas, thereby increasing radiation sensitivity and therapeutic efficacy [160,161].

These advances highlight nanotechnology’s crucial role in enhancing radiotherapy, improving tumor destruction, and reducing treatment-associated toxicity, ultimately leading to more effective cancer interventions [162].

4.2. Synergistic Effects of Nanoparticles with Chemotherapeutic Agents

Nanoparticles are revolutionizing chemotherapy by enhancing drug delivery, overcoming multidrug resistance (MDR), and improving therapeutic precision [163,164]. A major challenge in chemotherapy is the non-specific distribution of drugs, which often results in systemic toxicity and reduced efficacy. Nanoparticles circumvent this limitation by facilitating targeted drug delivery, ensuring higher drug concentrations at tumor sites whilst sparing healthy tissues [165,166].

Additionally, nanoparticles help combat MDR, a phenomenon in which cancer cells expel therapeutic agents via efflux pumps, such as P-glycoprotein, reducing drug effectiveness [167,168]. By bypassing these resistance mechanisms, nanoparticles improve intracellular drug retention, ensuring enhanced cancer cell destruction [169]. Moreover, nanoparticles can co-deliver chemotherapeutic drugs alongside MDR modulators, inhibiting efflux pathways and enhancing drug potency [170,171].

Nanoparticles also enable combination therapies, integrating chemotherapeutics with gene-silencing molecules (e.g., siRNA) [172] or immunomodulators [173,174] to target cancer through multiple mechanisms simultaneously. This multimodal approach disrupts tumor survival pathways, induces apoptosis, and strengthens immune responses [175].

Controlled drug release is another key advantage. Nanoparticles regulate therapeutic exposure, ensuring steady drug concentrations over extended periods, thereby reducing adverse effects and improving treatment adherence [176,177]. Additionally, stimuli-responsive nanoparticles, designed to release drugs upon exposure to pH, temperature, or enzymatic triggers, provide tumor-specific activation for optimal efficacy [178].

Together, these advances highlight nanoparticles’ vital role in modern chemotherapy, improving its efficacy, reducing toxicity, and overcoming resistance, ultimately leading to more effective cancer treatment strategies [179].

4.3. Role of Nanoparticles in Improving Photodynamic Therapy (PDT) Outcomes

Photodynamic therapy (PDT) is a minimally invasive cancer treatment that utilizes photosensitizers, light, and oxygen to generate ROS for tumor destruction [180]. Despite its potential, PDT faces limitations, including poor photosensitizer solubility, off-target effects, limited tissue penetration, and hypoxic tumor microenvironments [181,182]. Nanoparticles have emerged as key enhancers of PDT by improving their solubility, targeted delivery, tumor penetration, and controlled activation [183,184].

While this section focuses on PDT as a model system, the nanoparticle strategies discussed, such as enhanced solubility, targeted delivery, and tumor penetration, are not exclusive to PDT. These principles are equally applicable to other light-based therapies, like CALI, as well as conventional and emerging modalities, including chemotherapy, immunotherapy, and gene therapy. This underscores the versatility of nanotechnology for overcoming shared therapeutic barriers across diverse treatment platforms.

4.3.1. Improved Solubility and Bioavailability

Many photosensitizers suffer from poor aqueous solubility, limiting their therapeutic potential [185]. Nanoparticles, including liposomes, polymeric nanoparticles, and micelles, encapsulate hydrophobic photosensitizers, thereby enhancing their solubility, stability, and bioavailability, ensuring their efficient delivery to tumor sites [186].

4.3.2. Targeted Delivery

Nanoparticles can be functionalized with antibodies, peptides, or small molecules, enabling selective binding to tumor-specific receptors, thereby reducing off-target effects whilst enhancing photosensitizer accumulation in cancerous tissue [187,188].

4.3.3. Enhanced Tumor Penetration

The enhanced permeability and retention (EPR) effect allows for nanoparticles to accumulate preferentially in tumors due to their leaky vasculature [189]. Smaller nanoparticles penetrate deeper into tumor tissues, ensuring uniform photosensitizer distribution [190].

4.3.4. Overcoming Hypoxia

Hypoxic tumor microenvironments reduce ROS generation, weakening PDT’s effectiveness [191]. Oxygen-generating nanoparticles release oxygen in situ, alleviating hypoxia and enhancing therapeutic outcomes [192].

4.3.5. Controlled Release and Activation

Stimuli-responsive nanoparticles release photosensitizers in response to pH, enzymes, or light, ensuring localized therapy activation [193]. Additionally, upconversion nanoparticles convert near-infrared (NIR) light into visible light, enabling deeper tissue penetration [194].

4.3.6. Combination Therapies

Nanoparticles facilitate co-delivery of photosensitizers alongside chemotherapy, immunotherapy, or gene therapy, enhancing treatment efficacy and broadening the therapeutic potential [195].

These advancements underscore nanoparticles’ role in optimizing PDT, improving tumor targeting, therapeutic precision, and treatment efficacy [196].

4.4. Application of Chromophore-Assisted Light Inactivation (CALI) in Targeted Cancer Cell Therapy

Unlike the mechanistic breakdown used in Section 4.3 for PDT, CALI is presented here through a conceptual framework that highlights its therapeutic advantages and developmental limitations. This approach reflects CALI’s status as an emerging modality, where its clinical potential and translational challenges are best understood through a balanced evaluation of benefits and barriers. Accordingly, Section 4.4 is divided into two thematic subcategories: Section 4.4.1 discusses the therapeutic strengths of CALI, while Section 4.4.2 addresses the current limitations and prospects.

Chromophore-assisted light inactivation (CALI) is a novel therapeutic strategy that employs light-activated chromophores to selectively disrupt the biomolecules, proteins, or cellular structures associated with cancer cells [197,198]. This precision-driven method ensures localized cytotoxicity while sparing adjacent healthy tissues [199].

CALI operates through chromophore-conjugated molecules designed to bind to specific tumor-associated antigens or intracellular targets. Upon exposure to light, these chromophores generate reactive oxygen species (ROS) or other cytotoxic intermediates, triggering apoptosis or necrosis in the cancerous cells [200,201].

4.4.1. Therapeutic Advantages of CALI

• High Spatial Precision: Light-triggered activation ensures confined tissue damage, reducing collateral toxicity [202].
• Minimally Invasive Mechanism: Compared to conventional treatments like chemotherapy and radiotherapy, CALI offers localized action with fewer systemic effects [203].
• Molecular Versatility: Its targets range from oncogenic proteins to signaling nodes and metabolic pathways, enabling tailored therapeutic interventions [204,205].
• Combination Synergy: CALI can be integrated with photodynamic therapy (PDT) or nanoparticle-facilitated drug delivery systems to amplify its efficacy [206,207].

4.4.2. Limitations and Prospects

Despite its promise, CALI faces practical challenges, such as limited light penetration in deep tissues and issues surrounding chromophore stability and biocompatibility [208]. Emerging solutions include the use of near-infrared (NIR) light sources and nanoparticle-assisted chromophore delivery to enhance targeting and penetration [209,210].

5. Emerging Therapies in Cancer Treatment

A comprehensive overview of the molecular mechanisms underlying resistance to immune checkpoint inhibitors, highlighting the need for precision-guided interventions that can anticipate and overcome adaptive tumor responses has been reported [211]. Recent advances in cancer therapy have introduced highly innovative strategies aimed at targeting cancer cells with greater precision while minimizing damage to healthy tissues [212,213]. These emerging modalities, spanning immunotherapy, gene editing, epigenetic therapy, oncolytic virus therapy, therapeutic cancer vaccines, and stem cell therapy, are increasingly being revolutionized by nanotechnology. Nanomedicine platforms can enhance therapeutic efficacy by improving drug delivery, modulating immune responses, and overcoming biological barriers [214,215]. The following subsections detail how nanotechnology specifically contributes to each therapeutic domain.

5.1. Immunotherapy

Immunotherapy strengthens the body’s immune system to recognize and eliminate cancer cells. Established approaches include immune checkpoint inhibitors and CAR-T cell therapy [216,217]. Nanoparticles play a pivotal role as follows:

• Delivering immunomodulatory agents directly to immune cells.
• Enhancing CAR-T cell expansion through cytokine or gene payload delivery.
• Reducing systemic toxicity via tumor-targeted formulations.

5.1.1. Immune Checkpoint Inhibitors

PD-1/PD-L1 inhibitors (e.g., pembrolizumab, nivolumab) and CTLA-4 inhibitors (e.g., ipilimumab) have improved survival for melanoma and lung cancer [218,219,220,221]. Nanocarriers co-deliver checkpoint inhibitors with tumor antigens, enhancing immune activation and minimizing off-target effects.

5.1.2. CAR-T Cell Therapy

CAR-T therapy involves engineering T cells to target cancer antigens [222,223]. Nanoparticles facilitate this by delivering genetic constructs and stimulatory molecules, improving in vivo expansion and persistence.

Nanotechnology also supports biomarker-guided delivery systems to improve therapeutic precision and reduce immune-related adverse events [224,225].

5.2. Targeted Therapy

Targeted therapies inhibit molecular drivers of tumor growth [226]. Nanotechnology enhances these treatments by

• Improving the solubility and bioavailability of hydrophobic drugs.
• Enabling controlled release and tumor-specific accumulation.
• Facilitating combination strategies to overcome resistance.

5.2.1. Tyrosine Kinase Inhibitors (TKIs)

Drugs like imatinib (BCR-ABL) and gefitinib (EGFR) are effective in CML and lung cancer, while immune checkpoint pathways such as PD-L1 also play a critical role in tumor-induced immune suppression and therapeutic resistance [227,228,229]. Nanoformulations can improve the pharmacokinetics and enable sustained release, enhancing the therapeutic outcomes.

5.2.2. Monoclonal Antibodies

Trastuzumab targets HER2-positive breast cancer [230,231]. Nanoparticles conjugated with antibodies allow for dual targeting-receptor blockade plus cytotoxic payload delivery.

5.2.3. Small-Molecule Inhibitors

Vemurafenib targets BRAF mutations in melanoma [232]. Nanocarriers can enhance intracellular delivery and tumor penetration, addressing resistance mechanisms [233,234].

5.3. Gene Therapy

Gene therapy corrects cancer-driving mutations [235,236]. Nanotechnology is central to

• Protecting genetic material from enzymatic degradation.
• Facilitating cellular uptake and nuclear localization.
• Enabling non-viral delivery systems with reduced immunogenicity.

5.3.1. CRISPR-Cas9 Gene Editing

CRISPR-Cas9 enables precise DNA modifications, offering new avenues to investigate tumor mutational burden and mechanisms of immune evasion that influence cancer immunotherapy response [237,238,239]. Nanoparticles can deliver Cas9 and guide RNAs, improving the editing efficiency and reducing the off-target effects [240].

5.3.2. Tumor-Suppressor Gene Restoration

Restoring genes, like p53, promote tumor regression [241,242]. Nanocarriers can ensure localized delivery to tumor sites, enhancing the therapeutic specificity.

5.3.3. Immunogenomic Determinants of Checkpoint Inhibitor Response

Recent advances in immunotherapy have underscored the importance of immunogenomic profiling in predicting and enhancing responses to immune checkpoint blockade. Moreover, immunohistochemical quantification of PD-L1 expression on both tumor and immune cells provides a clinically validated biomarker to stratify patients for anti-PD-1/PD-L1 therapy and correlates with improved therapeutic outcomes [243]. Consequently, integrating immunogenomic biomarkers, including tumor mutational burden, neoantigen load, and immune gene signatures, enables precise patient stratification and improved selection for checkpoint inhibitor therapy [244]. However, the predictive value of PD-L1 expression remains nuanced; while elevated PD-L1 levels often correlate with improved responses, variability in detection methods and tumor heterogeneity complicate its utility as a standalone biomarker [245]. Tumor mutational burden (TMB) has emerged as a robust genomic indicator, with higher TMB linked to increased neoantigen load and enhanced immunogenicity, thereby improving the efficacy of checkpoint inhibitors across multiple cancer types [246].

5.4. Epigenetic Therapy

Epigenetic therapies modulate gene expression without altering DNA sequences [247,248]. Nanotechnology improves the following:

• Targeted delivery of epigenetic drugs.
• Drug stability and bioavailability.
• Synergistic effects through co-delivery platforms.

5.4.1. Histone Deacetylase (HDAC) Inhibitors

Checkpoint inhibitors can amplify antigen-specific T-cell activation and overcome tumor-induced immune suppression [249]. Building on this immunological foundation, vorinostat and panobinostat have been shown to reactivate silenced genes, offering promising avenues for epigenetic reprogramming in cancer therapy [250,251]. Nanoformulations of these agents further enhance tumor-specific accumulation and reduce systemic toxicity, improving therapeutic precision.

5.4.2. DNA Methyltransferase (DNMT) Inhibitors

Azacitidine and decitabine have restored gene expression in hematologic malignancies [252,253]. Nanoparticles can enable their co-delivery with other agents, amplifying their therapeutic synergy.

5.4.3. Modulating the Tumor Microenvironment for Enhanced Immunotherapy

The tumor microenvironment (TME) plays a pivotal role in shaping cancer progression and therapeutic response, particularly in the context of immunotherapy. Joyce and Fearon emphasized that the TME is not merely a passive backdrop but an active participant in tumor survival, immune evasion, and resistance to treatment, making it a compelling therapeutic target [254]. Notably, immunotherapeutic strategies can reprogram the TME to restore antitumor immunity, noting that the dynamic interplay between immune cells, stromal components, and signaling molecules determines the efficacy of checkpoint inhibitors [255]. Wei et al. further elucidated the fundamental mechanisms of immune checkpoint blockade, demonstrating how therapies targeting PD-1 and CTLA-4 pathways can overcome immunosuppressive barriers within the TME to elicit durable clinical responses [256]. Together, these insights underscore the necessity of integrating TME modulation into next-generation immunotherapeutic designs.

5.5. Oncolytic Virus Therapy

Oncolytic viruses selectively infect and destroy cancer cells [257,258]. Nanotechnology enhances this modality by the following:

• Improving viral stability and delivery.
• Facilitating deeper tissue penetration.
• Supporting combination therapies with immunomodulators.

5.5.1. Talimogene Laherparepvec (T-VEC)

T-VEC is FDA-approved for melanoma [259,260]. Nanoparticle carriers can improve its intratumoral delivery and immune activation.

5.5.2. Mechanisms of Action

• Direct Lysis: Viral replication leads to tumor destruction [261].
• Immune Activation: Antigen release recruits immune cells [262].
• Microenvironment Modulation: Enhances checkpoint inhibitor efficacy [263].

5.5.3. Tumor Microenvironment and Oncogenic Barriers to Immunotherapy

The tumor microenvironment (TME) plays a central role in shaping immune suppression and therapeutic resistance. Chen et al. highlighted how immunosuppressive cellular components within the TME, such as regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages, actively inhibit antitumor immune responses, thereby limiting the efficacy of immunotherapies [264].

Furthermore, it has been emphasized that the TME contributes to resistance against immune checkpoint blockade by fostering an immune-excluded phenotype and impairing T-cell infiltration [265]. In parallel, it has been demonstrated that tumor-intrinsic oncogenic pathways, including WNT/β-catenin signaling, can suppress immune recognition by preventing dendritic cell recruitment and CD8⁺ T cell priming, reinforcing immune escape mechanisms [266]. These insights underscore the need for therapeutic strategies that not only target immune checkpoints but also reprogram the TME and disrupt oncogenic signaling to restore immunogenicity.

5.6. Therapeutic Cancer Vaccines

Therapeutic vaccines stimulate immune recognition of cancer cells [267,268]. Nanoparticles can serve as

• Antigen carriers for cytotoxic T cell activation.
• Immune adjuvants to enhance the response durability.
• Platforms for personalized neoantigen delivery.

5.6.1. Mechanisms of Action

• Cytotoxic T Cell Activation: Nanocarriers deliver tumor antigens [269].
• Memory T Cell Generation: Sustains immune surveillance [270].
• Checkpoint Integration: Enhances response rates [271].

5.6.2. Examples of Therapeutic Cancer Vaccines

• Sipuleucel-T for prostate cancer [272].
• HPV-related vaccines for cervical and oropharyngeal cancers [273].
• KRAS vaccines for mutated tumors [274].

5.6.3. Mechanisms of Immune Escape and Resistance to Checkpoint Inhibitors

Despite the transformative impact of immune checkpoint inhibitors (ICIs), resistance remains a significant barrier to durable clinical success. It has been demonstrated that IL-10 can induce upregulation of TIM-3 on human T cells, leading to functional exhaustion and suppression of antitumor immunity [275]. This immunosuppressive signaling axis contributes to a hostile tumor microenvironment that undermines ICI efficacy. Paulson et al. further highlighted that therapy resistance in immunotherapy-treated cancers often arises from dynamic changes in antigen presentation, immune cell infiltration, and tumor-intrinsic adaptations that blunt immune recognition [276]. Complementing these findings, revealed that tumors can evade immune surveillance through transcriptional reprogramming and selective loss of checkpoint targets, reinforcing the complexity of resistance mechanisms and the need for combinatorial strategies to restore immune competence [277].

5.7. Stem Cell Therapy

Stem cell therapy regenerates damaged tissues and supports hematologic recovery [278,279,280]. Nanotechnology enhances the following:

• Stem cell tracking and imaging.
• Directed differentiation.
• Safe and efficient delivery to target tissues.

5.7.1. Applications for Cancer Treatment

• Hematopoietic Stem Cell Transplants: Restore blood cell production [281].
• Mesenchymal Stem Cells (MSCs): Exhibit anti-inflammatory and tumor-targeting properties [282].
• Induced Pluripotent Stem Cells (iPSCs): Enable patient-specific regenerative treatments [283].

5.7.2. Cellular and Metabolic Drivers of Immunotherapy Resistance

Overcoming resistance to cancer immunotherapy requires a nuanced understanding of the cellular and metabolic mechanisms that suppress immune function. It has been emphasized that immune cell exhaustion, marked by sustained expression of inhibitory receptors and diminished effector function can be pharmacologically modulated to restore antitumor immunity and improve therapeutic outcomes [284]. Furthermore, it has been documented how resistance to PD-1 blockade arises from multifactorial disruptions in antigen presentation, T-cell trafficking, and compensatory inhibitory pathways, necessitating combinatorial approaches to sustain immune activation [285]. Metabolic reprogramming within tumor cells also plays a critical role in immune escape, as Ho et al. demonstrated that altered glycolytic flux and nutrient competition can impair T-cell function and promote an immunosuppressive microenvironment [286]. Additionally, the role of tumor-associated macrophages (TAMs) in orchestrating immune suppression, angiogenesis, and therapy resistance, positioning TAMs as both biomarkers and therapeutic targets in the evolving landscape of immuno-oncology has been documented [287].

6. Immune Evasion and Therapeutic Resistance: Implications for Nanotheranostics

Cancer cells employ a diverse array of immune escape mechanisms that undermine the efficacy of immunotherapy, including downregulation of antigen presentation, secretion of immunosuppressive cytokines, and remodeling of the tumor microenvironment to exclude effector immune cells [288]. These adaptive responses not only facilitate tumor survival but also contribute to resistance against immune checkpoint inhibitors. Xiang et al. further emphasized that overcoming immunotherapy resistance requires multifaceted strategies, such as metabolic reprogramming, modulation of immune cell exhaustion, and rational combination therapies to restore immune competence and improve clinical outcomes [289]. While nanotheranostics offers a promising platform to deliver such interventions with precision, its clinical translation is hindered by limitations in long-term biocompatibility, regulatory standardization, and scalable manufacturing. Addressing these challenges will be critical to fully harness nanotheranostics as a vehicle for overcoming immune escape and resistance in next-generation cancer therapy.

6.1. Current Limitations in Nanotheranostics Applications

• Tumor Heterogeneity: Cancer cells exhibit diverse molecular profiles, complicating the design of universal nanotheranostic platforms. Tailoring nanoparticles to specific tumor subtypes remains a major hurdle [290].
• Biocompatibility and Long-Term Safety: Concerns persist regarding nanoparticle retention, clearance, and unforeseen toxicity. Longitudinal studies are essential to assess the chronic exposure risks and biodistribution [291].
• Manufacturing Scalability: Large-scale nanoparticle production demands standardized protocols to ensure reproducibility and batch-to-batch consistency for clinical applications [292].
• Regulatory Barriers: The approval process for nanomedicine lacks harmonized international guidelines, delaying clinical adoption and complicating global deployment [293].
• Economic Constraints: The high development costs for nanotheranostics, imaging technologies, and drug delivery systems limit accessibility, especially in low-resource settings [294].

Addressing these limitations will require interdisciplinary collaboration, regulatory reform, and cost-effective innovations to ensure the clinical integration of nanomedicine.

6.2. Future Research Opportunities and Potential Breakthroughs

Cancer research is advancing toward adaptive, programmable, and personalized nanomedicine platforms that will integrate nanotechnology with cutting-edge therapeutics to overcome biological barriers and improve patient outcomes [295,296].

Emerging Research Areas

• Programmable Adaptive Nanoparticles: Moving beyond static multifunctionality, next-generation nanoplatforms are being engineered to respond dynamically to tumor microenvironmental cues, such as pH, enzymatic activity, and hypoxia, to trigger site-specific drug release, imaging contrast enhancement, or immune activation in real time [297]. These platforms utilize modular design principles for customization across cancer types and therapeutic modalities.
• AI-Guided Nanomedicine Engineering: Artificial intelligence is increasingly being used to model nanoparticle–biological interactions, optimize surface functionalization, and simulate pharmacokinetics across diverse patient profiles [298]. Machine learning algorithms enable predictive design of nanocarriers with enhanced tumor penetration, reduced off-target effects, and tailored payload combinations, facilitating precision-guided nanotherapeutic development.
• Nanotheranostics-Enhanced Immunotherapy: Nanoparticles are being developed to deliver checkpoint inhibitors and tumor antigens directly to lymphoid tissues, enabling spatiotemporal control of immune activation [299]. Additionally, nanocarriers can modulate the tumor microenvironment to reverse immunosuppression, enhancing T cell infiltration and therapeutic durability.
• CRISPR-Cas9 and Nanomedicine Synergy: Non-viral nanoparticle carriers are being optimized for CRISPR-Cas9 delivery, enabling targeted genome editing with reduced immunogenicity and improved intracellular transport [300]. This synergy supports precise correction of oncogenic mutations and opens avenues for curative interventions in genetically driven cancers.
• Hybrid Imaging–Therapy Platforms: The integration of photoacoustic imaging with theranostic nanoparticles allows for real-time visualization of drug delivery and tumor response [301]. These dual-function platforms are advancing image-guided precision oncology by combining diagnostic and therapeutic capabilities in a single system.

With continued investment in research and technology, these innovations will redefine the boundaries of nanomedicine, enabling more effective, accessible, and patient-centered cancer therapies [302].

7. Discussion

The schematic diagram in Figure 1 illustrates the multifaceted role of nanotheranostics in cancer diagnostics and therapy, encompassing liposomes, polymeric micelles, dendrimers, virus-like particles (VLPs), and gold nanoparticles. These materials offer substantial advantages in targeted drug delivery, imaging, immune modulation, and multimodal therapy. The dendrimer molecule, with its branched polymeric structure, serves as a nanocarrier enabling photothermal therapy and gene delivery.

The immunotherapeutic potential of VLPs is especially relevant, as these engineered structures mimic viral capsids, efficiently delivering tumor-associated antigens. Gold nanorods, integral to photothermal therapy, enhance tumor imaging and ablation via laser-mediated heating. By combining therapeutic and diagnostic elements, nanotheranostics bridges molecular precision with enhanced treatment efficacy.

Figure 2 presents a mechanistic overview of chromophore-assisted light inactivation (CALI), where chromophores bind to tumor-associated proteins and initiate localized oxidative damage upon excitation. Light activation induces ROS generation, selectively disrupting cancer cells’ functioning while preserving the surrounding healthy tissues. This approach aligns with modern immune checkpoint therapies, as detailed in Figure 2, where molecular profiling of tumor epitopes enhances their immune-mediated destruction.

As highlighted in a recent report, the identification of actionable biomarkers has enabled the deployment of targeted treatments, including immune checkpoint inhibitors that modulate the PD-1/PD-L1 axis to restore antitumor immunity [303]. Specifically, these are agents such as nivolumab and pembrolizumab block PD-1 receptors on T cells, thereby reinvigorating immune responses against tumor cells; a mechanism that has demonstrated significant clinical efficacy in non-small cell lung cancer (NSCLC) [304,305,306]. These therapies not only exemplify the shift toward personalized oncology but also underscore the importance of molecular profiling in guiding treatment decisions [307].

These strategies complement CALI by amplifying cancer antigen exposure, improving tumor clearance through immune modulation. Immune checkpoint inhibitors such as atezolizumab, nivolumab, ipilimumab, durvalumab, and pembrolizumab have demonstrated significant efficacy across various cancer types by enhancing T cell-mediated antitumor responses. For instance, atezolizumab has shown superiority over chemotherapy in urothelial carcinoma [308], while the combination of nivolumab and ipilimumab has yielded promising outcomes in lung cancers with high tumor mutational burden [309]. Durvalumab, administered post-chemoradiotherapy, has improved survival in stage III NSCLC [310], and pembrolizumab has outperformed chemotherapy in PD-L1–positive NSCLC patients [311]. Nivolumab has also proven effective in previously treated NSCLC, offering a viable alternative to docetaxel [312]. Central to these therapies is PD-L1 expression, which serves as a predictive biomarker for response, guiding patient selection and optimizing therapeutic outcomes [313].

Liposomal drug delivery systems (Figure 3) have demonstrated structured encapsulation, targeted release, and prolonged drug circulation. The EPR effect enhances liposome accumulation in tumors, facilitating site-specific drug deployment whilst reducing systemic toxicity. Surface-functionalized liposomes, integrating targeting moieties, can improve cellular uptake in malignancies with known receptor overexpression. Liposomes thus serve as a key nanocarrier in chemotherapy and gene therapy applications.

The tumor microenvironment (TME), depicted in Figure 4, presents the barriers that limit conventional drug penetration and efficacy. Hypoxic conditions, an acidic pH, and the extracellular matrix density can restrict therapeutic access to cancerous tissues. Smart nanoparticles, including pH-sensitive liposomes and dendrimers, exhibit environment-adaptive drug release, responding dynamically to tumoral conditions. Gold nanorods and graphene-based nanocomposites, essential for photothermal therapy, can overcome dense extracellular structures via heat-induced disruption, increasing the therapeutic precision.

Figure 5 presents a pyramidal timeline capturing the major advancements in nanotheranostics, with each milestone contributing to the growing sophistication of cancer treatment strategies. This timeline chronicles the groundbreaking innovations, tracing the journey from the foundational theranostic concepts to modern multimodal applications in precision oncology. In 1988, the term theranostics emerged, heralding a paradigm shift by merging therapy and diagnostics into a unified approach to cancer management. This innovation enabled real-time monitoring of therapeutic responses, enhancing treatment adaptability and individualization. By 2005, gold nanoparticle-based imaging and photothermal therapy had revolutionized non-invasive cancer interventions. Gold nanoparticles, with their unique optical properties, facilitated tumor localization and selective ablation, marking a breakthrough in minimally invasive treatments. Moving forward, 2010 saw the expansion of polymeric micelle applications, significantly enhancing drug delivery efficiency. These nanocarriers improved their solubility and targeted release, reducing systemic toxicity and optimizing therapeutic precision in chemotherapy. A pivotal moment in 2015 was the introduction of virus-like particles (VLPs) into cancer immunotherapy. Engineered to mimic viral structures, VLPs stimulate robust immune responses, offering promising avenues for tumor antigen presentation and vaccine development. Their ability to activate adaptive immunity transformed the landscape of cancer immunotherapy. Finally, in 2024, an unprecedented leap in multimodal nanotheranostic systems enabled concurrent cancer imaging and therapy, marking a new frontier in personalized medicine. These integrated platforms now provide real-time monitoring, precision targeting, and dynamic adaptability, optimizing patient outcomes with minimized side effects. Through decades of continuous innovation, nanotheranostics has solidified itself as a foundational pillar in modern oncology, paving the way for next-generation therapies that will merge molecular precision with advanced therapeutic modalities.

8. Regulatory and Manufacturing Considerations in Nanomedicine Development

The translation of nanomedicines from the bench to bedside demands a harmonized framework that addresses regulatory, manufacturing, and safety dimensions. This section synthesizes the current perspectives on FDA/EMA regulatory guidance, manufacturing scalability, quality control, and post-market surveillance, while proposing structural enhancements for scientific reporting.

8.1. Regulatory Frameworks: FDA and EMA Guidance

Nanomedicines are regulated under existing medicinal product frameworks, yet their unique physicochemical properties necessitate tailored guidance. The FDA has issued several documents addressing nanomaterial use in drug products, including guidance on liposome drug products and nanomaterial safety in cosmetics and biologics [314]. The EMA, through reflection papers and multidisciplinary guidelines, has emphasized the need for early scientific advice and case-by-case evaluation, particularly for nanosimilars and complex hybrid systems [315]. Despite these efforts, a unified regulatory definition of nanomedicines remains elusive, complicating cross-border harmonization [316].

8.2. Manufacturing Scalability and Batch Consistency

Scaling nanopharmaceutical production presents formidable challenges. Techniques such as microfluidics, supercritical fluid processing, and high-pressure homogenization offer promise, but often suffer from reproducibility issues [317]. Batch-to-batch variability in nanoparticle size, surface charge, and drug loading can significantly impact the pharmacokinetics and therapeutic efficacy. Quality-by-design (QbD) approaches and real-time analytics are increasingly being advocated to mitigate these risks [318,319].

8.3. GMP Requirements and Quality Control Measures

Good Manufacturing Practice (GMP) compliance for nanomedicines requires rigorous control of critical quality attributes (CQAs), including the particle size distribution, zeta potential, and encapsulation efficiency [320]. The PIC/S Guide to GMP PE009-16 outlines the updated expectations for investigational and commercial nanomedicines, emphasizing validated analytical methods and robust documentation [321]. However, conventional QC tools often lack sensitivity for nanoscale features, necessitating advanced characterization platforms, such as dynamic light scattering, electron microscopy, and nanoparticle tracking analysis [322].

8.4. Nanotoxicity: Mechanistic Insights and Risk Assessment

Nanotoxicity remains a central concern in regulatory evaluation. Mechanistic studies have revealed that nanoparticles may induce oxidative stress, membrane disruption, autophagy dysregulation, and inflammatory cascades [323]. Omics-based approaches and organ-on-chip models are emerging as powerful tools to predict the long-term toxicity and off-target effects [324]. Regulatory bodies are increasingly calling for chronic exposure data and mechanistic validation to support safety claims [325].

8.5. Environmental Impact and Lifecycle Assessments

The environmental risk assessment (ERA) of nanomedicines is underdeveloped but gaining traction. Studies have highlighted the need for lifecycle-based evaluations, encompassing nanoparticle release during manufacturing, usage, and disposal [326]. The OECD Working Party on Manufactured Nanomaterials and the EMA’s Horizon Scanning Reports have advocated for standardized ERA protocols, including environmental persistence, bioaccumulation, and ecotoxicity testing. Lifecycle assessments (LCAs) have further underscored the importance of sustainable nanomanufacturing practices [327].

8.6. Post-Market Surveillance and Pharmacovigilance

Post-marketing surveillance (PMS) is critical for capturing rare adverse events and long-term safety signals [328]. Regulatory agencies, such as the FDA, EMA, and TGA, mandate periodic safety update reports (PSURs), risk management plans (RMPs), and real-world evidence collection [329]. However, nanomedicine-specific PMS frameworks are still evolving. Integration of AI-driven signal detection and patient registries may enhance vigilance and responsiveness [330].

8.7. Enhanced Manuscript Organization and Terminology Standardization

To improve clarity and accessibility, we recommend restructuring review manuscripts to progress from fundamental principles (e.g., nanoparticle design, physicochemical properties) to clinical applications (e.g., oncology, infectious diseases). An executive summary should distill the key findings and recommendations for the stakeholders. Additionally, a glossary of standardized terminology, covering terms such as “PEGylation,” “zeta potential,” “nanosimilars,” and “QbD”, will aid interdisciplinary comprehension.

9. Conclusions

The integration of nanotheranostics and emerging therapies is redefining cancer treatment, offering precision-targeted interventions, reduced toxicity, and real-time therapeutic monitoring. Whilst technical, regulatory, and economic barriers remain, ongoing scientific advancements are accelerating their clinical translation. Future research directions (including AI-driven diagnostics, adaptive nanocarriers, and immunotherapy synergies) will shape the next generation of oncology. By fostering interdisciplinary collaboration, refining clinical accessibility, and enhancing treatment customization, nanotheranostics is set to revolutionize cancer care, paving the way for more personalized, effective, and minimally invasive therapies [331].