Abstract

Ferroptosis-based therapy offers a promising strategy for aggressive breast cancer, yet its in vivo efficacy is frequently limited by insufficient oxidative amplification and poor local retention of catalytic agents. Here, we develop P_FeG@Gel, an injectable glucose-responsive nanozyme hydrogel that integrates mesoporous polydopamine (MPDA), glucose oxidase (GOX), and iron species within a thermo-responsive depot for localized photothermal-enhanced ferroptosis therapy. Mechanistically, GOX-driven glucose oxidation generates gluconic acid and H 2 O 2 , which fuel iron-mediated Fenton/Fenton-like reactions to amplify oxidative stress and lipid peroxidation, while 808 nm irradiation further accelerates catalytic activity through MPDA-mediated photothermal heating. In 4T1 breast cancer cells, P_FeG induces a ferroptosis-consistent phenotype characterized by SLC7A11 downregulation, ROS and lipid ROS accumulation, mitochondrial dysfunction, and elevated MDA levels, with rescue by ferrostatin-1. In vivo, intratumoral administration of P_FeG significantly suppresses tumor growth with favorable biosafety, whereas hydrogel encapsulation prolongs intratumoral retention, sustains photothermal responsiveness, and further enhances therapeutic durability. Together, this study establishes a localized ferroptosis-oriented therapeutic platform for breast cancer and highlights hydrogel-enabled retention as an effective strategy to enhance and sustain the in vivo performance of catalytic nanozymes.