Autophagy-mediated amplification of ferroptosis via a curcumin-loaded metal-enzyme nanoplatform for synergistic tumor therapy.

Ferroptosis is an iron-mediated cell death process driven by lipid peroxidation, yet its antitumor potential is often counteracted by the limited endogenous H2O2 content, the strict catalytic conditions required for the Fenton reaction, and protective autophagy. Notably, sustained autophagy drives ferritin degradation and iron release, thereby amplifying ferroptotic signaling. To exploit this mechanism, we designed a CD44-targeted nanoplatform, Cur@MG@HA, using hyaluronic acid for tumor-specific delivery. The system co-delivers glucose oxidase (GOx) and curcumin (Cur) within a Fe-Cu MOF. Following cellular uptake, GOx catalyzes the oxidation of intratumoral glucose to produce gluconic acid and H2O2. The acidic microenvironment promotes the Fe/Cu-mediated Fenton reaction, converting H2O2 into OH and initiating ferroptosis. The resulting oxidative stress induces autophagy, a process further potentiated by Cur. Enhanced autophagy accelerates ferritin degradation, thereby elevating labile iron levels and establishing a self-reinforcing cycle that amplifies lipid peroxidation, culminating in ferroptotic cell death. In vitro and in vivo experiments demonstrate that the self-reinforcing cycle between autophagy and ferroptosis significantly enhances tumor suppression. This study provides a mechanistic basis for synergistic therapy through redox-metabolic modulation and suggests that targeting iron-autophagy crosstalk with nanomaterials represents a promising strategy for cancer treatment.