Enzyme‐Guided Assembly Enables Precision Delivery of a Singlet Oxygen Battery for Membrane Lipid Peroxidation Therapy

Abstract

ABSTRACT Lipid peroxidation (LPO) of tumor cell membranes is a pivotal executor of regulated cell death and a potent trigger for antitumor immunity. However, most LPO inducing strategies either depend on external irradiation and adequate oxygen supply or require broad disruption of the glutathione (GSH)/glutathione peroxidase 4 (GPX4) antioxidant axis. As a result, their performance is often compromised by limited tissue penetration, heterogeneous tumor microenvironments, insufficient tumor selectivity with potential off target toxicity, and adaptive anti‐ferroptotic responses that blunt sustained LPO amplification. To address these challenges, we developed a precision enhanced singlet oxygen battery (SOB), termed GUIDE‐SOB. By integrating tumor‐specific recognition with enzyme guided, cell‐associated self‐assembly, GUIDE‐SOB achieves spatiotemporally confined oxidative therapy. This design anchors the oxidative source on the plasma membrane for more than 12 h and concentrates oxidative flux onto lipid rich membrane domains that are highly susceptible to peroxidation. Sustained membrane oxidation reduces reliance on light penetration and alleviates hypoxia associated limitations, while overcoming cellular repair mechanisms to produce robust tumor suppression. Overall, this work establishes a membrane‐targeted oxidative platform with prolonged activity, providing a promising strategy for treating deep‐seated and therapy‐resistant malignancies.