Iron-free ferroptosis-like nanoreactors for microenvironment-activated antibiofilm therapy via cascade lipid peroxidation amplification
- 1NHC Key Laboratory of Tropical Disease Control, School of Life Sciences and Medical Technology, The Second Affiliated Hospital, Key Laboratory of Emergency and Trauma of Ministry of Education, The First Affiliated Hospital, Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, 571199 China
- 2State Key Laboratory of Tropic Ocean Engineering Materials and Materials Evaluation, School of Materials Science and Engineering, Hainan University, Haikou, 570228 China
- 3Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, School of Basic Medical Sciences, Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, 571199 China
Abstract
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 (V2CTx), zinc peroxide (ZnO2), bovine serum albumin (BSA), and indocyanine green (ICG). Under acidic infection conditions, ZnO2 undergoes sustained decomposition to generate hydrogen peroxide and oxygen, while the multivalent V2CTx 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 (1O2) 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.
Graphical Abstract: A ROS nanoreactor responsive to the infected microenvironment. Under NIR irradiation, the nanoreactor releases H2O2 and Zn2+ upon microenvironmental triggering, providing Fenton reaction substrates for the vanadium autocycle states (V4+/V5+) in V2CTx to generate ·OH radicals. Further, ICG-induced 1O2 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.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12951-026-04851-y.
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BibTeX
@article{guo2026ironfree,
title = {{Iron-free ferroptosis-like nanoreactors for microenvironment-activated antibiofilm therapy via cascade lipid peroxidation amplification}},
author = {Zhengcai Guo and Zhiling Chen and Yang Li and Ziming Wei and Nan Zhang and Lidi Li and Yi Li and Qionglin Zhou and Lina Niu and Delun Chen and Yang Cao and Jinchun Tu and Rui Zhang and Qiang Wu},
journal = {Journal of Nanobiotechnology},
year = {2026},
month = jul,
doi = {10.1186/s12951-026-04851-y},
url = {https://doi.org/10.1186/s12951-026-04851-y},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Iron-free ferroptosis-like nanoreactors for microenvironment-activated antibiofilm therapy via cascade lipid peroxidation amplification
AU - Zhengcai Guo
AU - Zhiling Chen
AU - Yang Li
AU - Ziming Wei
AU - Nan Zhang
AU - Lidi Li
AU - Yi Li
AU - Qionglin Zhou
AU - Lina Niu
AU - Delun Chen
AU - Yang Cao
AU - Jinchun Tu
AU - Rui Zhang
AU - Qiang Wu
PY - 2026
DA - 2026/07/30
JO - Journal of Nanobiotechnology
DO - 10.1186/s12951-026-04851-y
UR - https://doi.org/10.1186/s12951-026-04851-y
AB - 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 (V2CTx), zinc peroxide (ZnO2), bovine serum albumin (BSA), and indocyanine green (ICG). Under acidic infection conditions, ZnO2 undergoes sustained decomposition to generate hydrogen peroxide and oxygen, while the multivalent V2CTx 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 (1O2) 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. Graphical Abstract: A ROS nanoreactor responsive to the infected microenvironment. Under NIR irradiation, the nanoreactor releases H2O2 and Zn2+ upon microenvironmental triggering, providing Fenton reaction substrates for the vanadium autocycle states (V4+/V5+) in V2CTx to generate ·OH radicals. Further, ICG-induced 1O2 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. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12951-026-04851-y.
SN - 1477-3155
ER -