Aug 2026· Journal of Colloid and Interface Science· Vol 725, pp.
141338
· 0 citations· 40 references
Medicine
TL;DR
This study provides a generalizable strategy for the rational design of programmable catalytic nanomedicines with integrated multifunctionality, and demonstrates efficient tumor targeting, robust tumor suppression, and favorable biosafety of in a 4 T1 breast cancer model.
Abstract
Metal-nanozyme-mediated chemodynamic therapy (CDT) has emerged as a promising strategy for the treatment of deep-seated tumors; however, its therapeutic efficacy is often limited by insufficient reactive oxygen species (ROS) generation and poor spatiotemporal control of enzyme-like activity within the tumor microenvironment (TME). Here, we report a biomimetic nanoplatform, CuO@MSN/TH302@GOx@CM (CMTGM), which integrates a programmed multi-enzyme cascade consisting of a copper oxide (CuO) core, a dendritic mesoporous silica (MSN) intermediate shell, the hypoxia-activated prodrug TH302, and surface-conjugated glucose oxidase (GOx). This hierarchical architecture enables stepwise activation and release of distinct enzyme-mimetic functions. Furthermore, CMTGM is cloaked with a homologous tumor cell membrane to enhance tumor-targeting capability. Following internalization of CMTGM into the tumor cells, GOx catalyzes glucose oxidation to generate H2O2 and gluconic acid, thereby disrupting tumor metabolism and acidifying the microenvironment, which accelerates MSN degradation and promotes the release of Evofosfamide (TH302) while exposing the CuO core. The Cu2+ ions released from the core exert glutathione peroxidase-like activity, depleting intracellular glutathione, and peroxidase-like activity, converting H2O2 into highly cytotoxic hydroxyl radicals, thereby amplifying CDT. Meanwhile, GOx-mediated oxygen consumption aggravates hypoxia and activates TH302, which further enhances therapeutic efficacy. This spatiotemporally programmed cascade involving substrate self-supply, responsive degradation, catalytic amplification, and prodrug activation eventually triggers multiple programmed cell death pathways and enhances immunogenic cell death, ultimately eliciting systemic anti-tumor immunity. In both in vitro and in vivo studies, CMTGM demonstrated efficient tumor targeting, robust tumor suppression, and favorable biosafety of in a 4 T1 breast cancer model. This study provides a generalizable strategy for the rational design of programmable catalytic nanomedicines with integrated multifunctionality.
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
BIMLM is developed as a biomimetic nanoplatform integrating lactate oxidase (LOX)-driven lactate exhaustion with MnO2-coated IR-780 for TME remodeling and self-amplifying ROS generation that enhances PDT/CDT efficacy while triggering metabolic starvation and ferroptosis, which collectively enable tumor eradication.
Boye Zhang, Yuli Chen, Pengyan Qiao et al.· Journal of Advanced Research· 0 citations
A biodegradable biomimetic nanoplatform (HMCDL@TK-M) was constructed by combining hydrogen-doped HxMoO3 nanoparticles, dual-drug loading, and a hybrid spinach-cancer cell membrane coating. The system features pH-responsive biodegradability, tumor-homing capability, and high NIR-II photothermal conversion. An oxygen-lactate cascade, formed via thylakoid membrane-mediated H2O2 decomposition and lactate oxidase-driven lactate oxidation, alleviates hypoxia and depletes lactate in the tumor microenvironment. This dual metabolic modulation reprograms M2 macrophages to M1, promotes dendritic cell maturation, and reduces Treg infiltration. In 4T1 tumor-bearing mice, HMCDL@TK-M achieves strong tumor accumulation, effective photothermal ablation, and combined with lactate depletion, complete tumor eradication without systemic toxicity. The treatment also induces robust CD4+/CD8+ effector memory T-cell responses, providing durable antitumor immunity. This work demonstrates a synergistic metabolic-photothermal immunotherapy strategy for efficient and long-lasting cancer treatment.
Shuo Gao, Yu Chen, Yan-Xi He et al.· Advanced Healthcare Material...· 0 citations
PANoptosis has emerged as a compelling strategy to potentiate antitumor immune responses. However, achieving specific PANoptotic cancer-cell death while sparing normal tissues remains a central challenge, as current strategies are constrained by inadequate spatiotemporal controllability and insufficient generation of key effector species, particularly reactive oxygen species (ROS). In this study, we report a class of PANoptosis nanoinducer constructed from atomically dispersed high-entropy metal sites, enabling spatiotemporally controlled near-infrared (NIR)-amplified cancer immunotherapy. The unique high-entropy metal-site configuration of the resulting nanozymes (HENA@PEG) boosts catalytic efficiency through atomic-level synergism, while enabling precise, pH-gated control over ROS generation via catalytic activation. In addition, nanozyme-mediated photothermal therapy (PTT) not only induces direct tumor ablation but also supplies exogenous thermal energy to accelerate the catalytic reactions. The co-programmed integration of endogenous and exogenous activations confers tumor-site-adaptive biocatalysis, thereby enabling precise spatiotemporal induction of PANoptosis. Both in vitro and in vivo investigations reveal that the resulting nanoinducer effectively promotes dendritic cell maturation and cytotoxic T-cell activation, ultimately amplifying antitumor immune responses and markedly suppressing 4T1 tumor progression. Overall, this work establishes a high-entropy-engineered nanoinducer that overcomes the limitations of nonspecific PANoptosis and immune evasion, representing a promising avenue toward more efficient and precisely targeted cancer immunotherapy.
Yue Zhao, Muchao Chen, Gaoxin Zhou et al.· Advances in Materials· 0 citations
Bioorthogonal chemistry provides a compelling strategy for in situ cytotoxin generation. However, the clinical translation of conventional bioorthogonal catalysts is impeded by poor tumor accumulation, insufficient targeting specificity, limited in vivo catalytic efficiency, and inadequate spatiotemporal control. Meanwhile, excessive lactate accumulation in the tumor microenvironment (TME) drives metabolic reprogramming, malignant progression, and therapeutic resistance. Here, we develop a living bacterial hybrid reactor by integratingShewanella oneidensis MR-1 (S.o) with Cu(II)-based zeolitic imidazolate frameworks to enable metabolism-guided and tumor-confined bioorthogonal catalysis. Exploiting the intrinsic hypoxia tropism of S.o, the hybrid reactor selectively accumulates within the TME. In the lactate-rich tumor, endogenous lactate drives bacterial reduction of inert Cu(II) to active Cu(I), enabling in situ catalyst activation and concurrent lactate depletion. The generated Cu(I) catalyzes a localized azide-alkyne cycloaddition between systemically administered prodrugs, producing a combretastatin A-4-like cytotoxin. Simultaneously, intracellular Cu(I) overload induces cuproptosis, while lactate depletion disrupts tumor metabolic homeostasis, together eliciting a synergistic triple antitumor effect. This work establishes a generalizable paradigm in which living bacterial vectors function as both tumor-targeting carriers and self-sustaining biochemical reactors, overcoming key limitations of conventional bioorthogonal catalysis and enabling precise, tumor-confined therapeutic activation.
Tumor immunotherapy has emerged as a transformative strategy for cancer treatment. However, its clinical efficacy remains limited by the immunosuppressive tumor microenvironment (TME), which restricts immune cells infiltration, suppresses effector cells activity, and promotes immune escape. Recent advances in catalytic nanomedicine have highlighted single-atom nanozymes (SAzymes) as a promising platform for overcoming these barriers. Owing to their atomic precision and tunable electronic structure, SAzymes exhibit highly efficient enzyme-like catalytic activities and enable precise regulation of the TME. Through catalytic therapy, SAzymes can alleviate hypoxia, regulate lactate accumulation, disrupt redox homeostasis, and reprogram immunosuppressive immune cells populations. Importantly, SAzyme-mediated catalytic therapy can induce immunogenic cell death (ICD), thereby enhancing antitumor immune responses. In addition, the well-defined atomic architecture of SAzymes provides a unique opportunity to establish quantitative structure-activity relationships (QSAR), enabling rational optimization of catalytic performance through modulation of their composition and coordination environment. This review systematically summarizes the mechanisms by which SAzymes remodel the TME and enhance cancer immunotherapy, discussing recent advances in atomic level design principles and multimodal synergistic therapy. Finally, current challenges and future perspectives, including machine learning-guided SAzymes design, biosafety and clinical translation, are discussed to guide the next generation of SAzyme-based catalytic immunotherapies.
Lulu Zhang, Mingming Yin, Bingxiong Wang et al.· Advanced Healthcare Material...· 0 citations
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