Nanomedicine-Integrated Phototherapy for Cancer Theranostics: A Systematic Review of Photoresponsive Materials, Mechanisms, and Clinical Translation.

Introduction
Cancer is among the most pressing health challenges globally and a leading cause of premature death across diverse sociodemographic contexts.1 Despite meaningful advances in oncology, conventional treatment modalities (including surgical resection, systemic chemotherapy, radiotherapy, and hormonal therapy) share inherent limitations that compromise treatment outcomes. These include limited tumor selectivity, dose-limiting off-target cytotoxicity, and susceptibility to therapeutic resistance mechanisms, most notably multidrug resistance (MDR), which substantially reduces the durability of treatment responses.2,3
The rise of nanomedicine has introduced transformative possibilities for cancer diagnosis and treatment.3,4 Among the most clinically relevant applications is cancer theranostics, an integrative paradigm that unifies diagnostic imaging with therapeutic intervention within a single nanoplatform system.5,6 Such multifunctional nanocarriers can simultaneously deliver diagnostic agents and therapeutic payloads to tumor sites, enabling real-time monitoring of treatment response. Critically, they can be engineered to respond to endogenous stimuli (such as tumor microenvironmental pH gradients, redox imbalances, and enzyme overexpression) or exogenous stimuli including light irradiation, ultrasound, and magnetic fields.6,7
Among phototherapy-based strategies, photodynamic therapy (PDT) and photothermal therapy (PTT) have attracted sustained attention as minimally invasive modalities with spatiotemporal precision.8–11 PDT employs photosensitizers that, upon activation at specific wavelengths, generate cytotoxic reactive oxygen species (ROS) capable of selectively killing tumor cells through oxidative damage, vascular disruption, and immune stimulation (Figure 1A).12,13 PTT, by contrast, relies on photothermal conversion agents that transform absorbed light energy into localized hyperthermia, causing thermal ablation of malignant tissue through protein denaturation and membrane disruption (Figure 1B).12,14 The mechanistic distinctions between PDT and PTT (including differences in oxygen dependency, light wavelength requirements, and clinical applicability) are compared in Table 1.

The convergence of nanotechnology with phototherapy has substantially improved the potency and selectivity of both modalities.14,17 Nanocarriers preferentially accumulate in tumors through the EPR effect, a consequence of aberrant tumor vasculature and impaired lymphatic drainage (Figure 1C).18,19 This passive targeting mechanism can be augmented by surface conjugation of tumor-specific ligands, further concentrating therapeutic agents at disease sites while limiting systemic exposure.20 Additionally, nanoplatforms can integrate multimodal imaging capabilities (including fluorescence, photoacoustic, and magnetic resonance imaging) enabling image-guided therapy and real-time response monitoring.12,21
Despite these advances, several barriers continue to limit the clinical translation of nanomedicine-integrated phototherapeutic agents (PTAs). Variability in EPR effect magnitude across tumor types and individual patients, concerns about long-term biocompatibility of non-biodegradable nanomaterials, manufacturing scalability, and inadequately defined regulatory pathways each present distinct challenges.22 Light penetration depth remains a fundamental physical constraint, particularly for deep-seated tumors requiring interstitial or endoscopic light delivery.8,23
The present systematic review aims to synthesize current evidence on nanomedicine-based PTAs for cancer theranostics across four interrelated research dimensions: (1) nanotechnology-driven innovations in nanocarrier design; (2) phototherapeutic agent development and mechanistic optimization; (3) engineering of photoresponsive nanomaterials; and (4) advances toward clinical translation. By critically evaluating research trends, persistent knowledge gaps, and emerging opportunities, this review provides a coherent framework for advancing nanomedicine-based phototherapy from preclinical proof-of-concept to clinical application.

Methodology

Review Protocol and Design
This systematic review was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, adapted for preclinical and translational research in nanomedicine. Although the protocol was not prospectively registered in PROSPERO or equivalent registries, methodological decisions regarding database selection, search terms, inclusion and exclusion criteria, and data extraction were defined a priori and applied consistently throughout the review process. The review was structured to synthesize evidence across four predetermined dimensions of nanomedicine-integrated phototherapy in cancer theranostics.

Research Dimensions Framework
Four interrelated research dimensions were defined to capture the breadth of nanomedicine-integrated phototherapy:
Dimension 1 (Nanotechnology Advancements): Innovations in nanocarrier design, surface functionalization, physicochemical characterization, and targeting strategies for enhanced tumor delivery.3,21
Dimension 2 (Phototherapeutic Agents): Development and optimization of photosensitizers for PDT and photothermal conversion agents for PTT, including molecular design principles, ROS generation mechanisms, and photothermal conversion efficiencies.12,13
Dimension 3 (Photoresponsive Materials): Integration of diverse photoresponsive nanomaterials (noble metals, carbon-based structures, metal oxides, semiconductors, and hybrid composites) with emphasis on structure-property relationships and material selection criteria.24,25
Dimension 4 (Clinical Translation): Synthesis of translational progress including preclinical validation, multifunctional platform development, combination therapy strategies, and barriers to clinical implementation.22,26

Literature Search Strategy
A comprehensive electronic literature search was conducted in PubMed/MEDLINE, Scopus, Web of Science, and Embase, covering publications from January 2000 through December 2024. The search strategy employed Boolean combinations of controlled vocabulary (MeSH terms) and free-text keywords, including: (“nanomedicine” OR “nanoparticle” OR “nanocarrier”) AND (“photodynamic therapy” OR “PDT” OR “photothermal therapy” OR “PTT”) AND (“cancer” OR “tumor” OR “neoplasm”) AND (“theranostic” OR “photosensitizer” OR “photothermal agent”). The search was limited to English-language, peer-reviewed publications. Conference abstracts, editorials, letters, and grey literature were excluded to maintain evidence quality.

Study Selection and Eligibility Criteria
Inclusion criteria were: (1) investigation of nanomedicine-based phototherapeutic strategies for cancer; (2) coverage of at least one of the four research dimensions; (3) reporting of original experimental data from in vitro, in vivo, or clinical studies; (4) provision of mechanistic information on phototherapy or nanoparticle design; and (5) publication in peer-reviewed English-language journals.
Exclusion criteria were: (1) purely theoretical or computational studies without experimental validation; (2) non-cancer phototherapy applications; (3) phototherapy without nanomedicine integration; (4) review articles, meta-analyses, or letters without original data; (5) inadequate methodological reporting; and (6) duplicate publications or redundant datasets.
Records were screened by title and abstract, followed by full-text review of potentially eligible studies. Disagreements were resolved by discussion among authors.

Data Extraction and Synthesis
Data were extracted systematically for each included study, covering: nanoparticle composition and physicochemical properties; phototherapeutic modality (PDT, PTT, or combined); light activation parameters (wavelength, power density, irradiation duration); experimental cancer model; efficacy metrics; mechanistic findings; and translational considerations. Given the substantial heterogeneity in experimental designs, nanomaterial compositions, cancer models, and outcome measures across included studies, quantitative meta-analysis was not feasible. A narrative synthesis approach was therefore adopted, organizing findings by research dimension and identifying cross-cutting themes, emerging trends, and knowledge gaps.

Quality Assessment and Heterogeneity
In the absence of a universally validated tool for preclinical nanomedicine studies, quality was assessed using the following indicators: rigor of nanoparticle physicochemical characterization; appropriateness of experimental models; inclusion of relevant controls and statistical analyses; transparency of limitations reporting; and biocompatibility assessment. Study heterogeneity (spanning in vitro cell culture systems, subcutaneous xenograft models, orthotopic animal models, and early-phase clinical investigations) was recognized as a primary constraint on data synthesis. Therapeutic outcomes reported across these different experimental contexts were interpreted accordingly, with particular caution applied to extrapolating preclinical efficacy data to human translational potential.

Results

Study Selection and Research Trends
From the initial database searches, 1847 records were retrieved. After removing 312 duplicates, 1535 records were screened by title and abstract, resulting in the exclusion of 1127 records that did not satisfy eligibility criteria. Full-text assessment of the remaining 408 records led to the exclusion of a further 330 studies (reasons: reviews without original data, n=154; non-cancer applications, n=89; insufficient methodology, n=87). A total of 78 studies met all eligibility criteria and were included in the final synthesis.
Analysis of publication trends across the included literature reveals three discernible phases of development in nanomedicine-integrated phototherapy. An exploratory phase (2000–2010) established foundational mechanisms and proof-of-concept studies. An acceleration phase (2011–2018) saw rapid diversification of nanomaterial classes and expansion of preclinical validation work. A translation-focused phase (2019–2024) has been characterized by increasing emphasis on multifunctional platform development, combination therapy strategies, and early-phase clinical evaluation. The proportional growth of clinical translation-focused publications during this final phase suggests progressive field maturation, though the absolute number of clinical studies remains small relative to the preclinical literature. Geographic contributions span Asia (China, South Korea, Japan), North America, and Europe, with increasing interdisciplinary collaboration across materials science, pharmaceutical sciences, and oncology.

Dimension 1: Nanotechnology Advancements in Cancer Diagnosis and Treatment
Contemporary nanomedicine platforms incorporate sophisticated design principles to address fundamental limitations in drug delivery. Nanocarrier size optimization within the 20–200 nm range has been established as critical for tumor targeting efficiency: particles smaller than 20 nm undergo rapid renal clearance, while those exceeding 200 nm demonstrate impaired tumor extravasation. Surface modification through PEGylation significantly extends circulatory half-life from minutes to hours or days by reducing opsonin binding and macrophage recognition. Emerging alternatives (including zwitterionic polymer coatings and biomimetic cell membrane camouflage) offer additional strategies to circumvent the limitations of PEGylation, such as the accelerated blood clearance (ABC) phenomenon.19,27
Distinct nanocarrier architectures offer complementary advantages. Lipid-based nanoparticles afford excellent biocompatibility, though photosensitizer loading capacity can be constrained. Polymeric nanoparticles provide tunable degradation kinetics and high drug loading. Inorganic nanoplatforms (particularly mesoporous silica nanoparticles and metal-organic frameworks, MOFs) offer exceptional surface areas and inherent therapeutic or imaging properties.12
The EPR effect, arising from abnormal tumor vasculature with fenestrations of 100–780 nm and impaired lymphatic drainage, enables passive nanoparticle accumulation at tumor sites, with preclinical models demonstrating tumor-to-normal tissue concentration ratios of 10–50-fold.18,19 However, human tumor studies reveal substantially greater EPR variability than animal models, with elevated interstitial fluid pressure and dense extracellular matrix further limiting tumor penetration. Active targeting through surface-conjugated ligands (including antibodies, peptides, and aptamers directed against tumor-overexpressed receptors) augments passive accumulation and improves binding specificity. Dual and multi-receptor targeting strategies have been explored to address tumor heterogeneity and enhance binding avidity.28,29
Theranostic nanomedicines integrate real-time diagnostic functionality alongside therapeutic payload delivery, enabling personalized treatment monitoring. Multimodal imaging modalities provide complementary information: fluorescence imaging (FLI) offers high sensitivity for superficial lesions (1–2 cm depth); photoacoustic imaging (PAI) achieves optical contrast with ultrasonic detection depth (3–5 cm); magnetic resonance imaging (MRI) provides unlimited penetration depth with high anatomical resolution; and computed tomography (CT) enables rapid whole-body assessment.12,21,30–32,77–79

Dimension 2: Phototherapeutic Agents and Mechanisms
PDT and PTT operate through mechanistically distinct pathways, each with unique dependencies on tumor physiology and distinct clinical applicability profiles, as summarized in Table 1 and illustrated in Figure 1A and B.
PDT exploits photosensitizer molecules that, upon irradiation at specific wavelengths, undergo electronic excitation from the ground singlet state (S0) through the excited singlet state (S1) to the long-lived triplet state (T1) via intersystem crossing. From the triplet state, two mechanistic pathways operate. Type I reactions involve electron or hydrogen transfer to substrate molecules, generating superoxide anion radicals (O2•⁻), hydroxyl radicals (•OH), and hydrogen peroxide (H2O2). Type II reactions involve direct energy transfer to molecular oxygen, generating highly cytotoxic singlet oxygen (1O2) as the predominant cytotoxic species. Both reaction types culminate in oxidative damage to cellular macromolecules, initiating apoptosis or necrosis, and also elicit vascular disruption and immunogenic responses.33,34
First-generation photosensitizers, exemplified by Photofrin (porfimer sodium), demonstrated clinical utility but were limited by poor NIR absorption and prolonged cutaneous photosensitivity (4–6 weeks). Second-generation agents overcame many of these drawbacks: chlorins (eg., Foscan) offer red-shifted absorption spectra and reduced photosensitivity; phthalocyanines exhibit strong NIR absorption; and bacteriochlorins enable deeper tissue penetration. Third-generation photosensitizers incorporate advanced functionalization strategies, including antibody conjugation for active targeting, nanoparticle encapsulation to improve aqueous solubility and tumor accumulation, and activatable designs that remain quenched until triggered by tumor-specific microenvironmental stimuli. Emerging photosensitizer classes include aggregation-induced emission (AIE) photosensitizers with enhanced ROS generation in the aggregated state, and two-photon photosensitizers that enable NIR-activated treatment of deeper tissue volumes.15
PTT converts absorbed NIR light into localized hyperthermia through plasmonic heating, non-radiative relaxation, or thermal vibration mechanisms (Figure 1B). Tumor temperatures of 41–48°C sustained over 5–30 minutes promote apoptotic cell death, while temperatures exceeding 48°C induce immediate necrosis through protein denaturation. A key advantage of PTT is its oxygen-independence: tumor hypoxia, a common feature of solid tumors that limits PDT efficacy, does not impair photothermal ablation. Photothermal conversion efficiency (PCE) represents the primary performance metric, with leading agents achieving values of 50–99%.12,35
Gold nanoparticles represent the most clinically advanced photothermal agents, combining tunable localized surface plasmon resonance (LSPR), high PCE (50–90%), favorable biocompatibility, and versatile surface functionalization.24,36 Nanoparticle morphology critically determines optical properties: spherical nanoparticles exhibit LSPR at 520–550 nm; nanorods with varying aspect ratios enable LSPR tuning across 600–1100 nm; nanoshells shift resonance into the NIR window; nanostars concentrate electromagnetic fields at sharp tips; and nanocages integrate drug-loading capacity with photothermal function.37
Carbon-based nanomaterials offer broad NIR absorption, high surface area for drug loading, and emerging biodegradability. Single-walled carbon nanotubes (SWCNTs) display diameter-dependent optical properties with PCE values of 50–80%, though biocompatibility concerns necessitate careful surface functionalization, typically through PEGylation. Graphene oxide (GO) provides improved aqueous dispersibility, while reduced graphene oxide (rGO) exhibits superior photothermal properties (PCE 40–70%). Size-optimized graphene quantum dots (less than 10 nm) address biodegradability concerns through enzyme-mediated degradation pathways.25,27,38,39

Dimension 3: Photoresponsive Nanomaterials – Inorganic and Organic Classes
The landscape of photoresponsive nanomaterials encompasses a diverse array of material classes, each with distinct physicochemical properties, optical behaviors, and therapeutic applications, as systematically summarized in Table 2.

Noble metal nanoparticles, particularly gold nanostructures, derive their distinctive optical properties from collective electron oscillations that produce localized surface plasmon resonance.48 Gold nanoparticles have emerged as the most translationally mature photothermal platform owing to their biocompatibility, surface functionalization versatility, and tunable plasmonic characteristics. Gold nanoshells have advanced furthest toward clinical application; the AuroLase Therapy system (Nanospectra Biosciences), comprising silica-gold nanoshells, has demonstrated technical feasibility, safety, and preliminary focal ablation efficacy in a Phase I clinical evaluation for prostate cancer.49 Bimetallic nanostructures incorporating silver, copper, or platinum with gold offer expanded optical tuning and potentially synergistic therapeutic effects.37,50
Carbon nanotubes (diameters 1–100 nm) exhibit strong NIR absorption with PCE values of 50–80%. SWCNTs possess diameter-dependent optical properties, whereas multi-walled CNTs (MWCNTs) offer superior mechanical stability. Surface PEGylation substantially improves colloidal stability, aqueous dispersibility, and systemic clearance profiles.38 Graphene and its derivatives benefit from exceptional specific surface area (theoretical maximum 2,630 m2/g), broad NIR absorption, and rich surface chemistry for functionalization. Graphene quantum dots (less than 10 nm) additionally offer photoluminescence properties and enzyme-mediated biodegradability.27,40
Metal oxide nanoparticles provide unique combinations of optical, electronic, magnetic, and catalytic properties. Copper sulfide nanoparticles (CuS, Cu2S) exhibit strong NIR absorption in the 900–1100 nm range with PCE values of 40–60% and offer a pathway to biodegradability through controlled copper ion release.41 Iron oxide nanoparticles combine superparamagnetic behavior (enabling MRI contrast and magnetic hyperthermia) with moderate photothermal activity.42 Transition metal dichalcogenides (MoS2, WS2) display layer-dependent bandgap tunability, NIR absorption, PCE values comparable to graphene (35–65%), and amenability to biodegradation through oxidative dissolution.44 Black phosphorus demonstrates promising photothermal performance (PCE 30–50%), layer-dependent bandgap tunability, and potential biodegradability through conversion to non-toxic phosphate species.43
Hybrid nanoplatforms integrate complementary materials to achieve synergistic therapeutic effects that exceed those of single-component systems. MOFs with exceptionally high surface areas (1,000–10,000 m2/g) and tunable porosity provide unprecedented photosensitizer loading capacities; porphyrin-based MOFs incorporating photosensitizer molecules as structural linkers maximize loading while avoiding aggregation-caused quenching.45 Core-shell architectures, such as Fe3O4@Au nanoparticles combining a magnetic core (MRI contrast, magnetic targeting) with a gold shell (PTT functionality, biocompatibility), exemplify the rational integration of diagnostic and therapeutic functions within a single nanoplatform.46,47
Recent investigations have also explored the potential of naturally derived and biocompatible photoresponsive materials. Plasmonic silver nanoparticles continue to attract attention for their versatile optical tunability in biological applications.51 Carbon quantum dot hybrid systems demonstrate high photocatalytic efficiency under visible-light activation, offering potential as scaffolds for next-generation photoresponsive nanocarriers.52 Moreover, plant-derived phytochemical compounds (including phenolic antioxidants and bioactive secondary metabolites from sources such as Myrtus communis) are increasingly investigated as biosynthesis templates for organic photosensitizers and photothermal agents with improved biocompatibility and reduced long-term toxicity.53

Dimension 4: Multifunctional Platforms and Clinical Translation
Contemporary nanomedicine increasingly emphasizes multifunctional platform engineering that integrates multiple treatment modalities with diagnostic functionality, as summarized for clinically advanced platforms in Table 3. Such approaches aim to address tumor heterogeneity and resistance mechanisms through simultaneous multi-target engagement, with treatment response monitored in real time.3,12

Phototherapy-chemotherapy combinations constitute the most extensively studied multimodal strategy, capitalizing on complementary mechanisms: phototherapy provides immediate local ablation and vascular disruption, while chemotherapy extends systemic coverage. Photothermal heating from PTT enhances drug release from thermosensitive nanocarriers and increases vascular permeability, potentially reversing MDR phenotypes. Preclinical studies consistently report superior therapeutic efficacy for co-loaded nanoplatforms relative to either monotherapy alone.
PDT-PTT combination strategies exploit mechanistic synergism: PDT-generated ROS augment photothermal agent efficacy, while hyperthermia from PTT increases tumor oxygenation and enhances PDT activity. Dual-wavelength irradiation protocols that co-activate both modalities achieve more complete tumor eradication at lower individual doses, potentially reducing systemic toxicity profiles.
The integration of phototherapy with immunotherapy represents an increasingly productive frontier. Phototherapy-induced immunogenic cell death (ICD) releases damage-associated molecular patterns (DAMPs) (including calreticulin, HMGB1, and ATP) that act as in situ vaccination signals, promoting dendritic cell maturation and cytotoxic T-lymphocyte priming. Combination with immune checkpoint inhibitors or immunostimulatory adjuvants amplifies systemic anti-tumor immunity, offering potential activity against distant metastases beyond the irradiated field.14,17
Despite extensive preclinical validation, clinical translation remains restricted to a small number of platforms (Table 3). Manufacturing scalability and batch-to-batch reproducibility present formidable challenges for complex multifunctional nanoplatforms, requiring GMP-compliant synthesis with stringent physicochemical quality control. Regulatory pathways for nanomedicine-based phototherapy are incompletely defined, with uncertainty regarding characterization requirements, toxicological evaluation protocols, and clinical trial design considerations for nanoparticle-based therapeutics.26,55
EPR variability in human tumors constitutes a particularly significant translational barrier. Preclinical xenograft models may substantially overestimate EPR-mediated nanoparticle accumulation achievable in human patients with diverse tumor types, prior treatment histories, and variable tumor microenvironments. This recognition has stimulated companion diagnostic development aimed at prospectively stratifying patients most likely to achieve adequate nanoparticle tumor accumulation.22,56
Despite these challenges, the AuroLase photothermal therapy system (AuroShell gold nanoshells, Nanospectra Biosciences) has demonstrated clinical feasibility for focal prostate cancer ablation. The 2019 PNAS pilot study in 16 patients demonstrated technical safety, precise thermal ablation of targeted tumor foci, and minimal collateral damage to surrounding urological structures. Subsequent trials (NCT02680535, NCT04240639) have collectively treated more than 100 patients as of 2023–2024, providing expanding evidence of clinical translatability.49 In PDT, multiple photosensitizer formulations carry regulatory approval: Photofrin (porfimer sodium) for esophageal, pulmonary, and bladder cancers; Levulan (aminolevulinic acid) for actinic keratosis; and Foscan (temoporfin) for head and neck malignancies, establishing important clinical and regulatory precedents.15,16

Discussion

Synthesis of Key Findings
This systematic review has delineated the current state of nanomedicine-integrated phototherapy for cancer theranostics across four research dimensions, revealing substantial advances alongside persistent translational barriers. The overall trajectory of the field reflects a progression from foundational photochemistry and proof-of-concept nanocarrier designs toward increasingly sophisticated multifunctional platforms with expanding clinical evidence bases.
The evolution of nanocarrier design from passive EPR-dependent strategies to active multi-receptor targeting and stimuli-responsive release systems represents a pivotal conceptual advance.28,29 Nonetheless, the magnitude of EPR-mediated tumor accumulation is substantially more variable in human tumors than in standardized preclinical animal models, reflecting differences in tumor vascularity, interstitial fluid pressure, and microenvironmental composition. This variability challenges the assumption that EPR-mediated passive targeting is universally sufficient as a therapeutic delivery mechanism.18,19
The mechanistic characterization of PDT and PTT pathways has reached considerable depth at the molecular and cellular levels, elucidating how light-activated nanomaterial systems generate cytotoxic ROS or localized hyperthermia.34,35 A particularly important insight has been the recognition that PDT efficacy is critically oxygen-dependent, motivating strategies to overcome tumor hypoxia through oxygen delivery systems or Type I photosensitizers capable of producing cytotoxic radicals via oxygen-independent radical transfer mechanisms.57,58 Similarly, the discovery that PTT-induced ICD can elicit systemic anti-tumor immunity has opened the concept of photoimmunotherapy, in which localized photothermal ablation serves as a tumor antigen release mechanism to prime immune responses against distant disease.14,17
The material diversity of photoresponsive nanomaterials (from noble metals to carbon allotropes, semiconductors, and hybrid composites) provides a versatile toolkit for matching optical properties, biocompatibility, and functional capabilities to specific clinical scenarios.24,42 Gold nanoplatforms retain an overall translational advantage owing to their biocompatibility and established surface chemistry, though concerns about long-term accumulation in reticuloendothelial organs continue to motivate parallel development of biodegradable alternatives.59 The classification and comparative performance data provided in Table 2 facilitate rational material selection for specific therapeutic goals.

Study Heterogeneity and Limitations of Evidence
A critical interpretive challenge throughout this synthesis is the profound heterogeneity of included studies. Experimental systems range from two-dimensional cell culture models to subcutaneous xenografts, orthotopic tumor models, and early-phase human trials. These contexts differ fundamentally in their ability to recapitulate the complexity of human tumor biology, including stromal interactions, immune infiltration, heterogeneous vascularity, and three-dimensional architecture.22 Subcutaneous xenografts, which constitute the majority of in vivo evidence, are acknowledged to overestimate EPR accumulation and therapeutic response relative to human tumors.
This heterogeneity has a direct bearing on data interpretation within this review. Findings from cell culture and animal studies cannot be directly extrapolated to predict human clinical efficacy. Therapeutic outcomes were accordingly contextualized within their respective experimental models, and translational claims were assessed conservatively. The preponderance of preclinical evidence relative to human data reflects the early developmental stage of many nanomedicine platforms rather than established clinical efficacy, and this distinction is important for calibrating expectations about near-term clinical impact.
Additional methodological variability exists in the reporting of nanoparticle characterization parameters, light delivery protocols, irradiation conditions, and efficacy endpoints across studies. This lack of standardization limits direct inter-study comparisons and highlights an important unmet need for consensus reporting frameworks in nanomedicine phototherapy research.

Theoretical and Clinical Implications

Theoretical Contributions
This review contributes to the theoretical understanding of cancer nanomedicine by assembling mechanistic insights across scales: from photochemical reactions at the molecular level, through cellular signaling cascades, to tissue-level therapeutic outcomes. The elucidation of structure-function relationships governing nanoparticle physicochemical properties and their consequences for biodistribution, cellular uptake, and therapeutic efficacy provides a rational framework for prospective platform design.60,61
The recognition that tumor microenvironmental characteristics (acidic pH, elevated glutathione, enzyme overexpression, and hypoxia) can serve as endogenous triggers for stimuli-responsive therapeutic activation represents a conceptual shift from systemic chemotherapy toward precision oncology.6,7 This framework extends beyond phototherapy to inform nanomedicine design more broadly. Furthermore, the emerging evidence that phototherapy-induced ICD can convert immunologically cold tumors into hot tumors susceptible to immune checkpoint blockade provides mechanistic rationale for rational combination immunotherapy strategies.14,17

Clinical Practice Implications
From a practical perspective, spatiotemporal light activation allows selective tumor destruction while sparing adjacent normal tissues, potentially reducing treatment-related morbidity compared with systemic chemotherapy or external beam radiotherapy.15,62 The minimally invasive nature of phototherapy (which can be delivered endoscopically or via percutaneous interstitial fiber placement) is particularly advantageous for tumors of the bladder, esophagus, airway, and prostate, and may enable outpatient delivery in appropriately selected patients.23,54
The theranostic paradigm (integrating real-time imaging feedback with therapeutic delivery) aligns with precision medicine principles by enabling individualized treatment monitoring and early identification of non-responders.63,64 This capacity for adaptive therapeutic management represents a meaningful advance over conventional modalities for which early response assessment is often limited.
However, practical implementation challenges remain substantial. Manufacturing complex multifunctional nanoplatforms with consistent batch-to-batch characteristics at clinical scale is technically demanding.55,65 Regulatory agencies have begun to develop frameworks for nanomedicine-specific evaluation, but standards for nanoparticle characterization, safety assessment, and clinical trial design remain incompletely harmonized across jurisdictions.66,67

Translational Barriers
Biocompatibility and long-term safety evaluation are prerequisite for clinical advancement, particularly for non-biodegradable inorganic materials with potential for hepatic and splenic accumulation.59 Comprehensive toxicological programs (encompassing acute toxicity, chronic exposure, immunogenicity, and delayed adverse effects) are resource-intensive but essential. The strategic development of biodegradable nanocarriers that degrade predictably after therapeutic action represents a priority direction to mitigate long-term accumulation concerns.41
EPR variability in human patients represents perhaps the most fundamental challenge to passive targeting strategies. Tumor vascular permeability varies considerably across cancer types and individual patients; certain human malignancies exhibit minimal EPR effect. Companion diagnostic tools that prospectively assess tumor vascular permeability or nanoparticle accumulation capacity could enable patient stratification, potentially improving clinical trial success rates by enriching study populations for predicted responders.22,56
Light penetration depth remains a physical constraint for PTT and PDT in deep-seated tumors. NIR wavelengths penetrate several centimeters of tissue and substantially expand the accessible treatment volume relative to visible light. Emerging solutions including X-ray-activated phototherapy, upconversion nanoparticles that translate NIR excitation to UV-visible photosensitizer activation, and radioluminescent nanoparticles may extend applicability to previously inaccessible tumor locations.68,69
Manufacturing complexity and associated cost considerations are barriers to commercialization. Multifunctional nanoplatforms incorporating therapeutic agents, targeting ligands, and imaging components require sophisticated synthesis protocols that may be difficult to scale while maintaining quality standards. Cost-effectiveness analyses comparing nanomedicine-based phototherapy with established treatments are notably absent from the current literature but will be essential for reimbursement decisions.66

Future Research Directions

Material Innovation
Priority research directions include the development of biodegradable nanocarriers maintaining robust phototherapeutic performance with predictable elimination after therapeutic action.59 Organic semiconducting polymer nanoparticles, MOFs with hydrolytically labile coordination bonds, and biomimetic nanocarriers incorporating natural cellular membranes represent promising approaches.44,47
Photosensitizer engineering should target further red-shifting of absorption spectra into the NIR window, increased singlet oxygen quantum yields, and improved photostability to expand applicability to deeper tumors.70,71 Development of Type I photosensitizers generating cytotoxic radicals through oxygen-independent pathways can circumvent hypoxia-related limitations of Type II PDT.72 Photothermal agent development should emphasize high PCE in the second NIR window (1000–1350 nm), which provides superior tissue penetration relative to NIR-I, alongside biodegradability.73,74

Mechanistic Understanding and Predictive Modeling
Advanced mechanistic investigation using single-cell analysis, spatial transcriptomics, and computational modeling would clarify relationships between nanoparticle properties, biodistribution, cellular uptake pathways, and therapeutic outcomes.6 Quantitative structure-activity relationship models could reduce empirical optimization burden and guide rational nanoplatform design. Investigation of tumor microenvironment remodeling induced by phototherapy (including effects on vasculature, extracellular matrix, stromal cell populations, and immune infiltration) would provide mechanistic insights to guide combination regimen design.20

Clinical Translation Strategies
Establishing consensus standards for nanoparticle characterization, toxicological evaluation protocols, and clinical trial design in nanomedicine-based phototherapy would substantially streamline regulatory review and accelerate translational pathways.66,67 International consensus efforts engaging researchers, clinicians, regulators, and industry partners are needed to harmonize these standards.
Companion diagnostic development to enable patient stratification based on predicted therapeutic benefit is a high-priority need.22 Imaging biomarkers of tumor vascular permeability, hypoxia status, or nanoparticle accumulation could prospectively identify patient subpopulations most likely to benefit from EPR-dependent nanomedicine interventions. Adaptive clinical trial designs incorporating biomarker-driven patient selection, real-time imaging endpoints, and pharmacokinetic-pharmacodynamic modeling would generate robust efficacy evidence while conserving resources.16

Integration with Emerging Technologies
Convergence of nanomedicine-based phototherapy with artificial intelligence for treatment planning, precision robotics for light delivery, and advanced imaging for real-time response assessment offers pathways to enhanced treatment precision.75 Machine learning applied to nanoparticle characterization datasets may identify non-obvious structure-function relationships that are difficult to discern through conventional experimental approaches.
Integration with immunotherapy (combining phototherapy-induced ICD with immune checkpoint inhibitors, adoptive cell therapies, or cancer vaccines) represents a particularly high-priority strategy for extending benefit to patients with metastatic disease.14,17 Biological targeting innovations, including tumor-homing cell-based nanoparticle carriers, pH-responsive and enzyme-responsive delivery systems, and biomimetic nanoparticles camouflaged with cellular membranes, may further enhance tumor selectivity and reduce off-target accumulation.6,76

Conclusion
This systematic review has synthesized evidence on nanomedicine-integrated phototherapy for cancer theranostics across four dimensions: nanotechnology advances, phototherapeutic mechanisms, photoresponsive nanomaterials, and clinical translation. The findings demonstrate that nanotechnology has fundamentally transformed phototherapeutic approaches by improving tumor targeting specificity, photosensitizer and photothermal agent delivery, and multimodal therapeutic-diagnostic integration.24,29
The mechanistic basis of PDT and PTT is well characterized: light-activated nanomaterials generate cytotoxic ROS or localized hyperthermia through distinct but complementary pathways, with substantial potential for synergistic combination.34,35 The diversity of photoresponsive nanomaterials (from gold nanostructures and carbon allotropes to biodegradable organic semiconductors) offers a broad toolkit for matching optical properties and functional capabilities to specific clinical contexts (Table 2). Multifunctional theranostic platforms integrating phototherapy with chemotherapy, immunotherapy, and multimodal imaging demonstrate synergistic efficacy in preclinical models and support real-time treatment monitoring.14,77
Despite significant preclinical advances, clinical translation remains limited by enduring barriers: EPR variability in human tumors, long-term biocompatibility uncertainties, manufacturing scalability demands, and incomplete regulatory frameworks.78,79 The clinical evaluation of gold nanoshell-mediated photothermal ablation (AuroLase Therapy) and the regulatory approval of multiple PDT photosensitizer formulations validate the translational feasibility of the nanomedicine phototherapy approach, while identifying clear opportunities for further optimization.
Future directions should prioritize biodegradable nanocarrier development, mechanistic characterization using advanced single-cell and computational methods, systematic integration with immunotherapy to leverage phototherapy-induced ICD, and AI-assisted treatment optimization.17,47 International collaborative networks supporting standardized evaluation protocols and multicenter clinical trials will be essential for accelerating knowledge generation and clinical implementation.
Nanomedicine-integrated phototherapy offers spatiotemporal control, tumor selectivity, and theranostic capability that address fundamental limitations of conventional cancer treatment. Realizing this clinical potential demands continued interdisciplinary innovation, rigorous translational validation, and strategic engagement with regulatory processes. The ongoing convergence of nanotechnology, photochemistry, tumor biology, and immunology constitutes a productive and evolving frontier in cancer therapeutics, provided that translational ambitions are grounded in realistic assessment of the gap between preclinical promise and clinical evidence.