Aug 2026· International journal of pharmaceutics· pp.
127296
· 0 citations· 66 references
Medicine
TL;DR
A structurally reinforced ternary redox-cycling nanoreactor that integrates Zr4⁺-stabilized zeolitic imidazolate framework-8 with redox-active Cu/Mn centers and ultrasmall Au nanodots achieves sustained ROS amplification, iron-homeostasis remodeling, and enhanced tumor-selective ferroptosis, offering a promising therapeutic strategy for TNBC.
Abstract
Triple-negative breast cancer (TNBC) lacks effective tumor-selective strategies, particularly limiting ferroptosis-based therapies that depend on oxidative stress. Here, we develop a structurally reinforced ternary redox-cycling nanoreactor that integrates Zr4⁺-stabilized zeolitic imidazolate framework-8 (ZIF-8) with redox-active Cu/Mn centers and ultrasmall Au nanodots, while co-loading paclitaxel (PTX) for acidic tumor microenvironment-responsive release. The Cu-Mn-Au interfaces enable rapid electron shuttling, sustaining multivalent metal cycling, accelerating Fenton-like reactive oxygen species (ROS) generation, depleting GSH, and promoting lipid peroxidation. Density functional theory (DFT) calculations further support its self-perpetuating redox mechanism. Dual surface modification with 4 T1 cell membranes and folic acid confers homotypic and receptor-mediated targeting. Mechanistic studies reveal coordinated GPX4/SLC7A11 suppression, PTX-enhanced cell-cycle arrest, and NCOA4/HO-1-mediated ferritinophagy, collectively amplifying ferroptosis. Unlike conventional metal-organic frameworks (MOFs), this Zr-reinforced trimetallic system maintains continuous redox cycling under reductive conditions. Overall, the nanoreactor achieves sustained ROS amplification, iron-homeostasis remodeling, and enhanced tumor-selective ferroptosis, offering a promising therapeutic strategy for TNBC.
In vitro and in vivo evaluations confirm that R-A/G@Z effectively suppresses aggressive breast tumors while maintaining a good safety profile, offering a promising strategy for intelligent metabolic-chemodynamic cancer nanomedicine.
Nianting Xiao, Xiao He, Daxiu Li et al.· Journal of Colloid and Inter...· 0 citations
Disrupting redox homeostasis is a feasible strategy for reversing immunosuppressive tumor microenvironment. Herein, by coating copper selenide (Cu2-xSe) on the surface of gold/molybdenum (AuMo), a AuMo@Cu2-xSe nanozyme with triple-enzyme activities of glucose oxidase/glutathione peroxidase/peroxidase was reported for inducing immunogenic cell death (ICD) and cuproptosis, thereby enhancing antitumor immunotherapy. Benefiting from the reversible valence transition of Mo6+/Mo4+ and Cu2+/Cu+, and the multi-enzyme activities, the reactive oxygen species (ROS) generation was enhanced, and the near-infrared II photothermal performance further promoted ROS generation, ultimately disrupting redox homeostasis. Moreover, by combining ROS storm and Cu2+ transportion, the mitochondrial dysfunction was triggered, which activated ICD and cuproptosis, releasing damage related molecular patterns and regulating cuproptosis-related proteins. Under a 1064 nm laser irradiation, the AuMo@Cu2-xSe nanozyme facilitated dendritic cells maturation, T cells infiltration, M1 macrophages polarization, and memory and regulatory T cells production. The developed AuMo@Cu2-xSe nanozyme provided a feasible strategy of integrating cuproptosis and photo/catalytic/immunotherapy, significantly suppressing primary and metastatic tumors for breast cancer.
Wei Wang, Zheng Niu, Longyue He et al.· Journal of Colloid and Inter...· 0 citations
Chemodynamic therapy (CDT), which harnesses the tumor microenvironment (TME), holds great promise for tumor treatment by generating reactive oxygen species (ROS) in situ. The efficacy of CDT relies on the efficient release and retention of transition-metal ions at the tumor site. Metal-phenolic networks (MPNs) provide an appealing platform for immobilizing metal ions within coordination architectures. Nevertheless, conventionally pre-assembled MPNs frequently suffer from inadequate targeted delivery. Here, we report an intelligent nanoplatform, DHU-MG@MnSiP, that unites dual TME activation with controlled in-situ coordination assembly. The platform comprises an acid-responsive Mn-doped hollow mesoporous silica encapsulating a hypochlorous acid (HOCl)-activatable polyphenolic pro-ligand (MB-GA). Under mildly acidic conditions, Mn ions and MB-GA are co-released. Subsequent HOCl cleavage of MB-GA liberates gallic acid (GA), driving the formation of a Mn-GA network and enabling regulated in-situ self-assembly. This weak coordination architecture increases local Mn retention and sustains a GA-assisted Mn(II)/Mn(III) redox cycle. The network dissociates in lysosomes to release Mn ions, thereby potentiating CDT. Concurrently, the HOCl-triggered release of methylene blue (MB) enables photodynamic therapy (PDT) to generate ROS, achieving synergistic CDT/PDT. This dual-trigger strategy provides precise activation and oxidative amplification within the TME, translating into robust in vivo antitumor effects. By shifting the construction of the active agent from pre-assembly in vitro to controlled in-situ formation at the lesion site, the present work exemplifies a programmable strategy that enables effective regulation of metal-ion retention and release.
Mingjie Jia, Gangqiang Wang, Jingyi Su et al.· Journal of Colloid and Inter...· 0 citations
A multifunctional nanoplatform by integrating a type I aggregation-induced emission photosensitizer (NTI) with a Cu-based nanozyme (MOF-Cu) enables efficient ROS generation, precise mitochondria targeting, and real-time fluorescence imaging, allowing more effective activation of ferroptosis and cuproptosis.
Jie Zhang, Bingbing He, Peihua Li et al.· Small· 0 citations
This nanoplatform integrates CPT chemotherapy, selenium intervention, and the p53 mutation background into a single system, establishing a toxicity-controlled, efficacy-enhanced strategy and reveals how selenium-based nanomaterials remodel redox homeostasis, bypass p53 deficiency, and reprogram apoptotic networks.
Cuiman Tang, Zhongjuan Wang, Yankun Liu et al.· ACS Nano· 0 citations
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
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