ROS-Responsive and Self-Amplifying polymeric prodrug for accelerating infected wound healing

Bacterial infection is a serious global health threat, and the clinical abuse of antibiotics has severe systemic toxicity and leads to multidrug-resistant bacteria. Stimuli-responsive polymers represent an encouraging strategy for intelligent treatment; however, inadequate polymer degradation and drug release are still challenging, especially in bacterial infection, where exponential rates of degradation and release are urgently needed. Here, we reported a facile 1,1,3,3-tetramethylguanidine (TMG)-promoted polyesterification method for the preparation of a novel antibiotic-free, PEGylated ROS-responsive polymeric prodrug of cinnamaldehyde (PRPCA), and demonstrated its remarkable intrinsic antibacterial activities and the acceleration of infected wound healing for the first time. The CA was covalently incorporated into the backbone of the polyester by a ROS-responsive thioacetal linkage and can be triggered to release by the ROS generated during bacterial growth. The released CA successively induced more ROS generation and the polymer achieved self-accelerating degradation via the positive feedback. The PRPCA-based nanomedicine possessed great bactericidal effects against both S. aureus and E. coli in vitro. Strikingly, the self-amplifying degradation of PRPCA nanoparticles caused abrupt "self-destruction" of S. aureus. More importantly, PRPCA significantly accelerated the S. aureus-infected wound healing process without systematic toxicity. Collectively, this work opens an avenue to develop novel self-amplifying stimuli-responsive polymers based on natural antimicrobial for superior wound disinfection and healing.