Aug 2026· International Journal of Nanomedicine· Vol 21· 0 citations· 349 references
Medicine
TL;DR
This review constructs a refined mechanistic framework to elaborate the complementary mechanisms of PDT and PTT toward CDT in terms of reaction kinetics modulation, endogenous substrate replenishment, and tumor antioxidant defense inhibition, and the key bottlenecks hindering clinical translation.
Abstract
Abstract Chemodynamic therapy (CDT) eradicates tumor cells by generating hydroxyl radicals (•OH) through Fenton/Fenton-like reactions, yet its therapeutic efficacy is severely constrained by intrinsic deficiencies of the tumor microenvironment (TME), including insufficient endogenous hydrogen peroxide(H2O2), suboptimal pH, robust glutathione (GSH)-mediated reactive oxygen species (ROS) scavenging, and tumor hypoxia. As potent synergistic modalities, photodynamic therapy (PDT) elevates oxidative stress via ROS overproduction, while photothermal therapy (PTT) accelerates Fenton reaction kinetics and improves intratumoral nanotherapeutic penetration, collectively remedying the inherent drawbacks of single CDT. Unlike conventional reviews that primarily catalogue nanomaterial diversity and classification, this review constructs a refined mechanistic framework to elaborate the complementary mechanisms of PDT and PTT toward CDT in terms of reaction kinetics modulation, endogenous substrate replenishment, and tumor antioxidant defense inhibition. We systematically overview the core synergistic principles of integrated nanosystems, covering ROS cascade amplification, GSH depletion-initiated ferroptosis, TME acidification, extracellular matrix (ECM) degradation, and immunogenic cell death. We further summarize recent advances in dual-modal PDT-CDT, PTT-CDT, and PDT-PTT-CDT synergistic nanoplatforms, and highlight the evolutionary trend of such nanotherapeutics-from primitive thermochemical coupling designs to advanced architectures with TME-responsive targeted delivery, second near-infrared (NIR-II) deep-tissue penetration, enzyme-cascaded self-substrate supply, and integrated theranostic functions. Moreover, the key bottlenecks hindering clinical translation are discussed, including limited light penetration depth, TME heterogeneity, suboptimal biosafety profiles, and inadequate clinical validation systems. Three pivotal priorities for future translational development are further proposed: the fabrication of NIR-II deep-penetrating nanoplatforms, the establishment of standardized manufacturing and quality control workflows for regulatory compliance, and the development of TME-adaptive, imaging-guided precision tumor delivery strategies.
Cerium molybdate-doped polyaniline nanoparticles are developed to enable a synergistic combination of photothermal therapy (PTT) and CDT, thereby triggering immunogenic cell death (ICD) and enhancing antitumor immunity and presenting a robust nanoplatform integrating chemodynamic and photothermal therapies for potent cancer immunotherapy.
Yulin Kuang, Cheng Lu, Bolan Yu et al.· Bioactive Materials· 0 citations
Despite advances in combined photothermal (PTT) and photodynamic (PDT) therapy for melanoma, therapeutic efficacy remains limited by tumor hypoxia, intracellular glutathione (GSH), insufficient tumor targeting, and photobleaching of photosensitizers. Herein, tumor-targeting and GSH self-depleting hyaluronic acid (HA)/tannic acid (TA)-engineered Prussian blue (PB) oxygen nanogenerators (ONs) loaded with IR780 (IHTPB ONs) are developed to enhance synergistic PTT/PDT. The IHTPB ONs exhibit uniform morphology, excellent colloidal stability, acidity/GSH-responsive IR780 release, high photothermal conversion efficiency (60%), and outstanding photothermal stability. Importantly, PB-mediated GSH oxidation and TA-mediated GSH conjugation enable dual-mode GSH depletion, while PB catalyzes oxygen generation to alleviate tumor hypoxia and promote IR780-mediated singlet oxygen production. Following CD44-mediated cellular uptake, IHTPB ONs effectively deplete intracellular GSH and, under near-infrared irradiation, induce robust reactive oxygen species generation and hyperthermia, leading to mitochondrial dysfunction, lipid peroxidation, apoptosis, and ferroptosis. In vivo, IHTPB ONs exhibit superior tumor accumulation and significantly enhanced antitumor efficacy compared with free IR780 and non-targeted nanoparticles, resulting in prolonged survival of melanoma-bearing mice. This work provides an effective nanoplatform integrating tumor targeting, oxygen self-supply, and dual-mode GSH depletion to potentiate synergistic PTT/PDT for melanoma therapy.
The antioxidant defense barrier in the tumor microenvironment, particularly glutathione (GSH), considerably restricts the therapeutic efficacy of chemodynamic therapy (CDT). Moreover, CDT generally exhibits relatively mild therapeutic efficacy owing to its intrinsic reaction kinetics, making it difficult to achieve complete tumor eradication within a short time. To address these issues, we construct a functionalized nanotherapeutic platform, Nb2CTx@Ru-PEG2000-FA (NCRPF), for tumor photothermal ablation and enhanced CDT resulting from GSH depletion. NCRPF possesses three key advantages: 1. Efficient near-infrared II photothermal conversion (η = 42.08%), raising the tumor temperature above 45 °C within 90 s for rapid ablation; 2. Dual peroxidase-like and glutathione peroxidase-like activities, simultaneously depleting GSH and generating a burst of ·OH to eliminate residual tumors; 3. Targeted tumor accumulation with 2.9-fold higher efficiency than passive diffusion. Both in vitro and in vivo results confirm that this combined strategy achieves complete tumor eradication with favorable biosafety. Collectively, the NCRPF nanotherapeutic system provides a powerful new paradigm with high translational potential for the complete eradication of breast cancer.
Achieving precise drug delivery to the tumor site can minimize systemic side effects caused by off-target effects. As a therapy that depends on oxygen content, photodynamic therapy (PDT) is significantly constrained by the hypoxic nature of the tumor microenvironment (TME). Compared with the limited efficacy of single PDT, the combination of multiple treatment modalities can achieve synergistic enhancement and superior therapeutic outcomes. Since carbon radical therapy does not rely on oxygen as a reactive substrate, it is mechanistically complementary to oxygen-dependent PDT. In this work, we report a novel strategy for developing a theranostic nanoplatform for long-lasting PDT activated by 1530 nm laser irradiation and glutathione (GSH)-triggered carbon-centered radical synergistic therapy that responds specifically to the TME. This theranostic nanoplatform (UCNPs@WOR:AF@CDC, UWAC) comprises three components: GSH-responsive engineered vesicles (CDC), functionalized metal-organic frameworks (WOR) encapsulating lanthanide upconversion nanoparticles (UCNPs@WOR, UW), and carbon radical prodrugs (ART-Fe, AF). Lanthanide-based upconversion nanoparticles (UCNPs) could upconvert 1530 nm light to 1390 nm for attenuation-minimized second near-infrared (NIR-II) fluorescence imaging and to visible light that serves as the light source for photocatalysis for water oxidation. The 1530 nm light-activated generation of reactive oxygen species (ROS), enhanced by UW-mediated hydrolytic oxygen evolution, works in synergy with the GSH-triggered release of the carbon radical prodrug (AF) to achieve long-lasting therapeutic outcomes. Importantly, it could achieve tumor-specific drug release, triggered by the degradation of the engineered vesicles in response to elevated GSH levels. This work develops a novel theranostic nanoplatform, which could achieve GSH-activated drug delivery, deep-tissue penetration, and a long-lasting therapeutic effect.
Jitong Gong, Yu Liu, Qingkun Yang et al.· ACS Applied Materials and In...· 0 citations
The oxygen heterogeneity within tumors restricts the therapeutic efficacy of hypoxia-activated prodrugs (HAPs) and traditional photosensitizers (PSs) when administered alone. To overcome this limitation, we present an oxygen-unrestricted synergistic therapeutic strategy to concurrently potentiate treatment efficacy in both hypoxic and normoxic tumor compartments. By introducing TEMPO, we developed an efficient PS capable of simultaneous Type I and Type II photocatalytic reactions. This PS, named DT, was co-encapsulated with the HAP TH-302 into a tumor-targeting nanoparticle system, DT@TH302, which exhibits mitochondrial localization. Upon photoactivation, DT@TH302 generates substantial amounts of singlet oxygen and superoxide anion, while disrupting the cellular NAD+/NADH redox equilibrium, leading to catastrophic mitochondrial dysfunction. The oxygen consumption during photodynamic therapy (PDT) further aggravates local hypoxia, thereby activating TH-302 to induce DNA cross-linking and promote tumor cell apoptosis. Meanwhile, DT-mediated PDT remains effective through a hypoxia-tolerant Type I mechanism. Moreover, the treatment triggers immunogenic cell death, demonstrating considerable potential for immunotherapy. In vivo, DT@TH302 exhibits excellent biosafety and tumor-targeting capability, resulting in significant tumor growth suppression. This work provides an oxygen-unrestricted synergistic strategy to compensate for the limitations of standalone Type II PSs or HAPs monotherapy, offering valuable insights for clinical cancer treatment.
High-precision tumor theranostic systems capable of real time monitoring are imperatively required for optimizing the spatial targeting accuracy during radiotherapy and surgical resection across clinical management of nasopharyngeal carcinoma (NPC). However, the clinical application of photodynamic therapy (PDT) is impeded by the suboptimal reactive oxygen species (ROS) generation efficiency and inadequate visualization of redox procedure. In this study, we developed a theranostic platform HSF, featuring integrated tumor-specific near-infrared (NIR) fluorescence imaging and photodynamic ROS generation for real time monitoring and targeted radiotherapy of solid malignancies for NPC. Mechanistically, HSF was initially activated by the elevated glutathione (GSH) levels in the tumor microenvironment, which concomitantly turned on its NIR fluorescence and photodynamic properties. The resulting NIR fluorescence allowed for tumor visualization, while the PDT-triggered oxidative stress further consumed intracellular GSH, thereby ultimately inducing ferroptosis. In NPC cell-derived xenograft models, HSF demonstrated exceptional biocompatibility and effective in vivo retention. This multifunctional photosensitizer enabled precise radiotherapy navigation via real time fluorescent monitoring and ferroptosis-mediated therapeutic mechanisms, offering a transformative approach for real time visualization-guided NPC therapy.
Fan Zheng, Yan Mo, Jingmei Zhou et al.· Small· 0 citations