Iron-free ferroptosis-like nanoreactors for microenvironment-activated antibiofilm therapy via cascade lipid peroxidation amplification

Ferroptosis-like nanotherapeutic strategies have emerged as promising approaches for eradicating bacterial biofilms; however, conventional iron-based nanotechnologies are often constrained by limited intracellular iron accumulation, enhanced bacterial antioxidant defenses, and insufficient oxidative substrates under hypoxic infection microenvironments. Herein, we report an iron-free ferroptosis-like antibacterial nanoreactor constructed by integrating vanadium carbide MXene (V 2 CT x ), zinc peroxide (ZnO 2 ), bovine serum albumin (BSA), and indocyanine green (ICG). Under acidic infection conditions, ZnO 2 undergoes sustained decomposition to generate hydrogen peroxide and oxygen, while the multivalent V 2 CT x backbone mediates Fenton-like redox cycling and depletes intracellular glutathione, collectively disrupting bacterial redox homeostasis. Upon near-infrared (NIR) irradiation, ICG produces abundant singlet oxygen ( 1 O 2 ) to initiate lipid peroxidation, and the accompanying photothermal effect further accelerates oxidative reaction kinetics within the confined nanoreactor. This cascade-amplified process enhances membrane lipid peroxidation, resulting in ferroptosis-like membrane collapse and irreversible bacterial death. Comprehensive mechanistic investigations, including membrane integrity analysis, radical scavenging assays, and oxidative lipidomics, identify lipid peroxidation as the dominant lethal pathway, characterized by extensive remodeling of arachidonic acid-, linoleic acid-, and omega-3 polyunsaturated fatty acid-derived oxidation products. Notably, the nanoreactor demonstrates potent therapeutic efficacy in infected wounds and abscess biofilm models while simultaneously alleviating inflammation and promoting tissue regeneration. Collectively, this work establishes a controllable and amplifiable iron-free ferroptosis-like antibacterial paradigm, substantially expanding the design scope of ferroptosis-inspired therapies and highlighting nanoreactor engineering as a powerful strategy for precisely regulating oxidative lethality against drug-resistant bacterial biofilm infections. A ROS nanoreactor responsive to the infected microenvironment. Under NIR irradiation, the nanoreactor releases H 2 O 2 and Zn 2+ upon microenvironmental triggering, providing Fenton reaction substrates for the vanadium autocycle states (V 4+ /V 5+ ) in V 2 CT x to generate ·OH radicals. Further, ICG-induced 1 O 2 generation coupled with photothermal effects significantly accelerates membrane lipid peroxidation and irreversible bacterial death. This cascading self-amplifying ROS generation strategy effectively disrupts biofilms of drug-resistant bacteria, demonstrating superior anti-infective and skin regenerative performance.