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

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.