In vivo antimicrobial therapeutic efficacy and immune homeostasis analysis of S. aureus peritonitis

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 nanomedicine 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 O2-• generation, while minimizing off-target organelle effects. We demonstrate application in S. aureus-infected sepsis showing high type-I ROS levels for antibacterial function from the nanomedicine to restore redox and immune homeostasis without noticeable toxicity. This work pioneers a strategy to convert ROS generation from type-II to type-I pathways for hypoxia-tolerant bacterial elimination, merging mechanistic precision with translational potential for clinical sepsis management.