Photoimmunologic Therapy of Stubborn Biofilm via Inhibiting Bacteria Revival and Preventing Reinfection

Abstract Stubborn biofilm infections pose serious threats to public health. Clinical practices highly rely on mechanical debridement and antibiotics, which often fail and lead to persistent and recurrent infections. The main culprits are 1) persistent bacteria reviving, colonizing, and rejuvenating biofilms, and 2) secondary pathogen exposure, particularly in individuals with chronic diseases. Addressing how to inhibit persistent bacteria revival and prevent reinfection simultaneously is still a major challenge. Herein, an oligo‐ethylene glycol‐modified lipophilic cationic photosensitizer (PS), TBTCP‐PEG7, is developed. It effectively eradicates Methicillin‐Resistant Staphylococcus aureus (MRSA) under light irradiation. Furthermore, TBTCP‐PEG7‐mediated photodynamic therapy (PDT) not only conquers stubborn biofilm infections by downregulating the two‐component system (TCS), quorum sensing (QS), and virulence factors, thereby reducing intercellular communication, inhibiting persistent bacterial regrowth and biofilm remodeling but also prevents reinfection by upregulating heat shock protein‐related genes to induce immunogenetic cell death (ICD) and establish immune memory. In vivo, TBTCP‐PEG7 efficiently eradicates MRSA biofilm adhered to medical catheters, stimulates angiogenesis, reduces inflammatory factor expression, and accelerates wound healing. Furthermore, ICD promotes short‐term immune and long‐term immunological memory for coping with secondary infections. This two‐pronged strategy not only effectively overcomes stubborn, persistent and recurrent biofilm infection, but also provides theoretical guidance for designing the next generation of antibacterial materials.