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

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 (pQM) intermediate. This mechanism creates a dual-action cascade: generating a potent ROS offense while simultaneously scavenging glutathione (GSH) via pQM, 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.