Crystallinity-Gradient Etched Hollow Mesoporous Zinc Nanoparticle for Dual-Source H₂O₂-Driven Tumor Ferroptosis Therapy.

Abstract

Zn²⁺ 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 H₂O₂ surge-driven tumor ferroptosis therapy. In acidic tumor microenvironment, Zn²⁺, H₂O₂, HEM, and GP can be released from HEM@HMZN@GP. The released Zn²⁺ damages mitochondrial electron transport chain (ETC) and generates superoxide anions (•O₂ ^-), which can be rapidly catalyzed by superoxide dismutase into H₂O₂. The dual-source of H₂O₂ markedly elevates local oxidative stress. HEM can be enzymatically converted by heme oxygenase‑1 to Fe²⁺, which reacts with the abundant H₂O₂ via Fenton reaction to produce hydroxyl radicals, initiating lipid peroxidation and ferroptosis. GP enhances T₁‑weighted magnetic resonance imaging signals, facilitating drug delivery visualization in tumors.