Dual‐Light‐Primed GSH‐Scavenging Lipid Hybrid Nanoplatform for Cascade‐Activated Photodynamic Therapy

ABSTRACT Photodynamic therapy (PDT) is often hindered by poor tumor selectivity and inefficient drug delivery. Herein, a lipid‐hybridized phototherapeutic nanoplatform, LBCIN, is presented to overcome these barriers by integrating a reactive oxygen species (ROS)‐triggered molecular logic gate with a synergistic dual‐light strategy. The molecular core consists of BdTT‐BNBE, a novel photosensitizer prodrug designed for tumor microenvironment‐selective activation. Upon triggering by endogenous ROS, BdTT‐BNBE undergoes cleavage to release the active photosensitizer and a para ‐quinone methide ( p QM) intermediate. This mechanism creates a dual‐action cascade: generating a potent ROS offense while simultaneously scavenging glutathione (GSH) via p QM, thereby systematically dismantling the tumor's antioxidant defense. For stable delivery, the payload is encapsulated within a chondroitin sulfate‐based core with a lipid corona, offering superior colloidal stability and CD44‐mediated targeting. Furthermore, a unique dual‐light sequence is employed to maximize efficacy. Initial 808 nm laser irradiation activates the carrier‐conjugated indocyanine green derivative (psICG), providing a “photothermal priming” effect that enhances membrane permeability and nanoparticle uptake. This facilitates subsequent white light‐emitting diode (LED) irradiation, triggering a potent PDT effect amplified by intermolecular energy transfer and ferroptosis induction. This engineered integration of ROS‐responsive chemistry and sequential light activation results in durable tumor eradication with a high safety profile.