Crystallinity‐Gradient Etched Hollow Mesoporous Zinc Nanoparticle for Dual‐Source H ₂ O ₂ ‐Driven Tumor Ferroptosis Therapy

ABSTRACT Zn 2+ offers significant advantages for cancer therapy via mitochondrial disruption, immune activation, and metal homeostasis perturbation, but faces challenges of rapid clearance and systemic toxicity. Existing zinc‑based (e.g., zinc oxide (ZnO), and zinc peroxide) nanoparticles often lack internal voids and sufficient surface area, restricting drug loading and functionalization. In this study, we developed a crystallinity‑gradient selective etching method to tailor biodegradable hollow mesoporous zinc nanoparticle (HMZN). Typically, zinc peroxide nanoparticles with low‑crystallinity core and high‑crystallinity shell were synthesized, and ammonia water was used to selectively etch the inner low‑crystallinity core, producing HMZN. Hemin (HEM) and Gd‑poly(acrylic acid) macrochelates (GP) were then loaded to construct HEM@HMZN@GP for dual‐source H 2 O 2 surge‐driven tumor ferroptosis therapy. In acidic tumor microenvironment, Zn 2+ , H 2 O 2 , HEM, and GP can be released from HEM@HMZN@GP. The released Zn 2+ damages mitochondrial electron transport chain (ETC) and generates superoxide anions (•O 2 − ), which can be rapidly catalyzed by superoxide dismutase into H 2 O 2 . The dual‐source of H 2 O 2 markedly elevates local oxidative stress. HEM can be enzymatically converted by heme oxygenase‑1 to Fe 2+ , which reacts with the abundant H 2 O 2 via Fenton reaction to produce hydroxyl radicals, initiating lipid peroxidation and ferroptosis. GP enhances T 1 ‑weighted magnetic resonance imaging signals, facilitating drug delivery visualization in tumors.