Enzyme-enhanced albumin-stabilized nanopolymers for cascade catalysis-driven ferroptosis-immunotherapy

Ferroptosis, an iron-dependent form of programmed cell death, holds significant promise for cancer therapy due to its unique redox-driven mechanism and immunogenic potential. However, its therapeutic efficacy is often compromised by inadequate catalytic kinetics and an unfavorable tumor microenvironment. Here, we develop a multifunctional nanocatalyst (BCuP@G) based on albumin-stabilized polypyrrole doped with multivalent Cu ions and conjugated with glucose oxidase (GOx) to enable enzyme-enhanced cascade catalysis for ferroptosis-immunotherapy. The embedded Cu⁺/Cu²⁺ redox centers catalyze glutathione depletion and ·OH generation, while GOx continuously supplies H₂O₂ through glucose oxidation. Upon NIR-II laser irradiation, the photothermal effect further accelerates both enzymatic and catalytic kinetics, triggering excessive redox imbalance, lipid peroxidation, and synergistic ferroptosis-apoptosis. Moreover, BCuP@G demonstrates effective tumor accumulation and potent antitumor efficacy, particularly in combination with anti-PD-1 therapy, which promotes tumor-associated macrophage repolarization and T cell infiltration. This study presents a robust cascade-catalytic nanoplatform that integrates redox modulation and immune activation for advanced ferroptosis-enhanced cancer immunotherapy.