Cerium molybdate-doped polyaniline nanoplatform for GSH-depletion-enhanced chemodynamic/NIR-II photothermal synergistic therapy via ferroptosis and immune activation
Aug 2026· Bioactive Materials· Vol 67, pp. 371 - 386· 0 citations· 49 references
Medicine
TL;DR
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.
Abstract
Chemodynamic therapy (CDT) holds great promise for tumor treatment by catalyzing endogenous hydrogen peroxide (H2O2) into cytotoxic reactive oxygen species (ROS). However, its efficacy is severely compromised by glutathione (GSH)-mediated ROS scavenging and intrinsically slow reaction kinetics. To address these limitations, we developed cerium molybdate-doped polyaniline nanoparticles (MoCe@PANI NPs) to enable a synergistic combination of photothermal therapy (PTT) and CDT, thereby triggering immunogenic cell death (ICD) and enhancing antitumor immunity. Mechanistically, MoCe@PANI NPs deplete intracellular GSH and generate abundant ROS via Ce4+/Mo5+/Mo6+-mediated redox cycles, leading to mitochondrial dysfunction and amplified ferroptosis. Crucially, near-infrared II (NIR-II) laser irradiation induces localized hyperthermia, which simultaneously executes PTT and accelerates the Fenton-like reaction kinetics, further intensifying ferroptotic cell death. This combinatorial strategy effectively activates tumor-associated immune responses, achieving effective ablation of primary tumors and eliciting a systemic abscopal effect that suppresses untreated distant metastases. Collectively, this study presents a robust nanoplatform integrating chemodynamic and photothermal therapies for potent cancer immunotherapy.
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.
Yuxuan Ma, Jie Gong, Zixuan Wu et al.· International Journal of Nan...· 0 citations
Chemodynamic therapy (CDT), which employs •OH generated by Fenton-type reactions to trigger cancer cell death, has received much attention in recent years. However, CDT efficacy is restricted by insufficient H2O2 levels and reactive oxygen species (ROS) consumption by antioxidants in tumor cells. Amplification of intracellular oxidative stress is an effective strategy for enhancing CDT efficiency. In this study, chitosan (CS)-protected iron peroxide nanoclusters (CS@FeNCs) were prepared via the reaction of Fe2+ and H2O2 in CS medium, and the resulting product can release H2O2 and convert H2O2 to •OH through the Fenton reaction under acidic conditions. To suppress the consumption of ROS by glutathione (GSH), gold nanoclusters templated by histidine (His) (His@AuNCs) were used to scavenge intracellular GSH by forming GSH@AuNCs. Furthermore, a nanocomposite was fabricated by encapsulating CS@FeNCs and His@AuNCs with polyvinylpyrrolidone (PVP), and the resulting PVP@Fe–Au can effectively amplify the level of oxidative stress in tumor cells by providing H2O2 and depleting GSH, which induced cancer cell apoptosis and death. It is hoped that the developed PVP@Fe–Au can provide an efficient strategy for designing high-efficiency CDT agents via boosting ROS generation and suppressing the antioxidation system.
Wenying Mi, Mingkun Jin, Xiaoting Yang et al.· Langmuir· 0 citations
Cancer therapeutic strategies centered on synergistic ferroptosis and cuproptosis have attracted considerable interest. However, current approaches predominantly relying on Fe and Cu sources face limitations including single mode of reactive oxygen species (ROS) production, poor organelle targeting, and lack of imaging capabilities. Herein, we developed a multifunctional nanoplatform, NMC NPs, by integrating a type I aggregation-induced emission photosensitizer (NTI) with a Cu-based nanozyme (MOF-Cu). This design enables efficient ROS generation, precise mitochondria targeting, and real-time fluorescence imaging, allowing more effective activation of ferroptosis and cuproptosis. Upon cellular uptake, MOF-Cu framework dissociates and releases NTI, which selectively accumulates in mitochondria. Under 635 nm laser irradiation, NTI generates type I ROS, triggering lipid peroxidation and activating ferroptosis. Simultaneously, MOF-Cu nanozyme exerts dual peroxidase-like and glutathione peroxidase-like activities, catalyzing H2O2 into hydroxyl radicals while depleting glutathione and releasing Cu+ ions, further promoting ferroptosis. Notably, the released Cu+ ions further disrupt mitochondrial function, induce dihydrolipoamide S-acetyltransferase aggregation, and activate cuproptosis. The synergistic action efficiently enhances immunogenic cell death. In vivo studies confirmed the potent antitumor efficacy of NMC NPs with minimal side effect. This study provides new insights into the cooperative regulation of metal-dependent cell death and advances the design of integrated theranostic nanoplatforms.
Jie Zhang, Bingbing He, Peihua Li et al.· Small· 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.
Acute kidney injury (AKI) is driven by a vicious interplay among excessive reactive oxygen species (ROS) accumulation and persistent renal hypoxia, which collectively disrupt redox homeostasis and exacerbate tubular injury. However, current therapeutic strategies primarily provide supportive care and fail to simultaneously modulate these interconnected pathological stressors. Herein, we report a cerium-doped rosmarinic acid nanosystem (RA/Ce NPs) formed via self-polymerization that catalytically eliminates ROS while simultaneously generating oxygen to reprogram the pathological renal microenvironment. The ultrasmall RA/Ce NPs enable efficient chelator-free 89Zr radiolabeling for positron emission tomography (PET) imaging. Redox-switchable Ce3+/Ce4+ centers confer robust catalytic activity and ROS-responsive biodegradation, ensuring potent antioxidation with safe clearance. RA/Ce NPs suppress intracellular ROS, preserve mitochondrial membrane potential, and protect against oxidative injury in vitro. In rhabdomyolysis-induced AKI mice, PET imaging reveals pronounced renal accumulation, while treatment markedly alleviates tubular damage, oxidative stress and hypoxia, leading to restored renal function with excellent biocompatibility. This work presents a natural-product-derived catalytic nanoplatform integrating antioxidation, oxygenation, imaging and biodegradability, offering a promising strategy for precision therapy of AKI.
Yajie Zhao, L. Hao, Jessica C. Hsu et al.· Bioactive Materials· 0 citations