Cascade-responsive biomimetic nanoparticles remodel tumor metabolism and potentiate ferroptosis for synergistic therapy of aggressive breast cancer

One-pot biomineralization co-encapsulates ART and GOx, overcoming delivery paradoxes. • RBCm coating prolongs circulation and enhances tumor accumulation. • GOx-driven starvation generates acidity, which in turn amplifies ART-mediated Fenton-like ROS production. • Released Zn 2+ sensitizes ferroptosis via a dual FPN1/p53 regulatory axis. • The integrated metabolic-oxidative strike suppresses aggressive breast cancer growth in vivo. 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 (H 2 O 2 ) and protons. This localized acidification accelerates structural degradation, supplying ample H 2 O 2 to fuel an ART-triggered Fenton-like reaction. Crucially, the concurrent liberation of Zn 2+ 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. pH-responsive R-A/G@Z co-delivers GOx and ART. GOx depletes glucose to generate H + and H 2 O 2 , accelerating ZIF-8 degradation and fueling ART-mediated Fenton reaction. Released Zn 2+ downregulates FPN1 to trap iron and upregulates p53 to suppress SLC7A11-GPX4, triggering synergistic ferroptosis in breast cancer. Download: Download high-res image (164KB) Download: Download full-size image