Aug 2026· Journal of Colloid and Interface Science· Vol 725, pp.
141315
· 0 citations· 45 references
Medicine
TL;DR
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.
Abstract
Breast cancer presents a formidable global health challenge, with traditional monotherapies frequently hampered by limited specificity and off-target toxicity. Herein, we developed a highly integrated, biomimetic, and pH-responsive zeolitic imidazolate framework-8 (ZIF-8) nanoplatform, RBCm-coated nanoparticles (R-A/G@Z), tailored for cascaded starvation and potentiated ferroptosis therapy. Through a one-pot biomineralization approach, the hydrophobic ferroptosis inducer artesunate (ART) and the hydrophilic metabolic enzyme glucose oxidase (GOx) were co-encapsulated within a ZIF-8 framework, followed by red blood cell membrane (RBCm) surface cloaking. The R-A/G@Z platform demonstrates enhanced tumor accumulation and undergoes acid-triggered disassembly within the tumor microenvironment (TME). Upon internalization, GOx-mediated glucose oxidation serves to starve the tumor of its primary energy source while continuously generating hydrogen peroxide (H2O2) and protons. This localized acidification accelerates structural degradation, supplying ample H2O2 to fuel an ART-triggered Fenton-like reaction. Crucially, the concurrent liberation of Zn2+ from the ZIF-8 lattice orchestrates a dual-regulatory axis: it downregulates ferroportin 1 (FPN1) to retain reactive iron intracellularly, and upregulates tumor protein p53 (p53) to suppress the solute carrier family 7 member 11-glutathione-glutathione peroxidase 4 (SLC7A11-GSH-GPX4) antioxidant shield. This integrated strategy overcomes the tumor's redox defenses, leading to ferroptotic cell death. 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.
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.
Beibei Sun, R. Wan, Runwei Wang 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
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.
Wanmei Zhou, Zixin Wang, Chengdong Nie et al.· International journal of pha...· 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
Chemoresistance, inadequate tumor targeting, and severe systemic toxicity remain key barriers to effective breast cancer treatment. Ferroptosis-inducing strategies have emerged as a promising therapeutic avenue, yet their efficacy is frequently compromised by the intrinsic antioxidant defense system and insufficient immune activation within the tumor microenvironment (TME). Herein, a hyaluronic acid (HA)-functionalized, berbamine (BBM)-loaded iron-based metal-organic framework (MOF) nanoplatform (HA-FeTCPP@BBM, HAFTB) was engineered. This nanosystem executes a "three-in-one" synergistic strategy that coordinates FeTCPP-mediated sonodynamic therapy (SDT), iron-dependent chemodynamic therapy (CDT), and BBM-mediated chemotherapy and ferroptosis sensitization, while HA functionalization facilitates tumor-oriented delivery to enhance the induction of ferroptosis-associated immunogenic cell death in triple-negative breast cancer (TNBC). Upon ultrasound (US) exposure, the HAFTB scaffold functions simultaneously as a sonosensitizer and an iron source. Ultrasound activation initiates sonodynamic reactions and enhances Fenton-like catalytic activity, substantially boosting reactive oxygen species (ROS) generation. Moreover, the localized release of BBM contributes to glutathione peroxidase 4 (GPX4) suppression and weakens the cellular antioxidant defense system, thereby sensitizing tumor cells to ferroptotic stress. This tripartite oxidative stress results in extensive lipid peroxidation and robust ferroptotic cell death. Abundant damage-associated molecular patterns (DAMPs) are concurrently released, supporting the occurrence of ferroptosis-associated immunogenic responses and subsequent immune activation. In an orthotopic TNBC mouse model, HAFTB integrated with SDT achieves pronounced tumor suppression with low systemic toxicity, while transcriptomic profiling supports the involvement of ferroptosis- and oxidative stress-related pathways. Overall, the principal advance of this cascade nanoplatform lies in the coordinated integration of FeTCPP-mediated SDT, iron-dependent CDT, and BBM-associated ferroptosis sensitization within an HA-assisted MOF delivery system, providing a promising therapeutic strategy for TNBC.
Current clinical interventions for solid tumors are confronted with multiple prominent challenges, including intratumoral hypoxia, constitutively activated endogenous antioxidant defense systems, and inefficient tumor targeting. In this study, a multifunctional nanoliposome carrier is developed by co-encapsulation of hemoglobin (Hb), ferric citrate (FC), and chlorin e6 (Ce6), and surface-modified with the iRGD (CRGDKGPDC) peptide to facilitate active tumor targeting and enhance subsequent intratumoral penetration. Under ultrasound irradiation, the iRGD-targeted nanoliposomes can efficiently generate two distinct types of reactive oxygen species (ROS) to produce strong synergistic cytotoxicity against 4T1 breast cancer cells via separate pathways: singlet oxygen (1O₂) through the sonodynamic therapy (SDT) pathway, and hydroxyl radicals (·OH) through the chemodynamic therapy (CDT) pathway. In vivo experimental results show that tail vein injection (i.v.) of iRGD-targeted nanoliposomes combined with external ultrasound irradiation achieves can significantly enhance tumor growth inhibition, which is attributed to triggered on-demand drug release induced by ultrasound. The as-prepared iRGD-targeted nanoliposomes exhibit remarkable synergistic antitumor efficacy, inducing extensive tumor necrosis, apoptosis, and ferroptosis while causing minimal systemic side effects, demonstrating great application potential for future breast cancer therapy.
Runming Zhong, Yingzhe Wu, Yanzhen Lou et al.· Colloids and Surfaces B: Bio...· 0 citations