Ultrasound-Triggered Type I Supramolecular Photosensitizer for Precise In Situ Chemiluminescence-Based Photodynamic Cyclic Therapy

Chemiluminescence-based photodynamic therapy (CL-PDT) addresses the challenge of traditional PDT regarding limited light penetration depth. However, its therapeutic efficacy is constrained by the efficiency of chemiluminescence resonance energy transfer (CRET) and CL intensity. Herein, we introduce a hypocrellin derivative into Ru(II) metallacycle to construct a novel supramolecular CL-based photosensitizer (PS), RDL, for the first time. RDL integrates an efficient type I Ru(II) PS acceptor and superoxide anion radical (O₂^•-)-responsive CL donor via coordinate covalent bonds, exhibiting excellent spectral overlap between the two components. More importantly, this strategy effectively minimizes the distance between the components, achieving a high CRET efficiency of 97%. Notably, RDL effectively generates hydroxyl radical (•OH) and O₂^•- under ultrasound (US) activation. Simultaneously, O₂^•- generated by RDL, along with that overexpressed in inflammation sites, synergistically triggers CL ligand to emit strong fluorescence, which activates Ru(II) PS to produce abundant •OH and O₂^•-. Herein, O₂^•- can be converted into •OH via CRET-mediated PDT cycle, which is the most reactive and toxic ROS in biology. Additionally, the US-induced cavitation effect enhances CL intensity, thereby achieving US-triggered and intramolecular CRET codriven in situ cyclic CL-PDT. To enhance the targeting efficiency of RDL, we construct biomimetic targeting nanoparticles, RDL@RM NPs, by coating with hybrid cell membrane shells. The RDL@RM NPs enable precise targeting of inflammation sites, thereby effectively eradicating pathogens in deep hypoxic tissues via CL-PDT. This research lays the groundwork for the development of US-triggered supramolecular CL-based PSs and their application in treating deep-seated bacterial infections.