Structural Superimposition

Abstact

Type-I photosensitization addresses the dilemma of intracellular bacterial hypoxia-induced photodynamic therapeutic (PDT) inefficacy, yet precise targeting and eradicating sequestered pathogens remains a formidable challenge. Herein, we engineer an albumin-based photodynamic conversion nanoparticles integrating target-specific recognition with controlled antibacterial functions to precisely eliminate intracellular pathogens and restore infected cell activity. Mechanistic studies reveal a vertically-crossed conformation that promotes intramolecular electron transfer and charge separation, redirecting photosensitizer (PS) reactivity toward type-I reactive oxygen species (ROS) generation. Electron-rich albumin further enhances cationic PS(+*) recycling, photostability, and O(2) (-*) production, while its selective cytoplasmic delivery via receptor/charge interactions enables preferential accumulation in intracellular bacteria, with reduced off-target organelle engagement. We demonstrate application in S. aureus-infected sepsis showing high type-I ROS levels for antibacterial function from the nanoparticles to restore redox and immune homeostasis without noticeable toxicity. This work pioneers a conformationally-gated ROS conversion approach for eliminating intracellular bacterial infections, merging mechanistic precision with therapeutic potential for clinical sepsis management.