Indolicidin‐Decorated Photosensitizer for Enhanced Antibacterials and Accelerated Diabetic Wound Healing

Abstract

ABSTRACT Diabetic wounds are difficult to heal due to infections caused by multidrug‐resistant bacteria. Although photodynamic therapy (PDT) and antimicrobial peptides (AMPs) have emerged as promising alternatives, each faces inherent limitations: PDT‐generated reactive oxygen species (ROS) have an extremely short lifespan (10–320 ns) and limited diffusion (10–55 nm), while AMPs are structurally unstable, potentially cytotoxic at high doses, and even induce bacterial resistance. To overcome these drawbacks, we developed a synergistic nanoplatform by integrating the AMP Indolicidin with the photosensitizer PTBT, further encapsulated within a thermosensitive F127 hydrogel (PTBT/I@F127). The system formed uniform, highly photosensitive nanoparticles in which Indolicidin, located on the outer surface, first disrupted bacterial membranes, facilitating the contact of PTBT with bacteria. Subsequently, abundant ROS were generated for rapidly killing bacteria under an 808‐nm laser irradiation, which effectively compensated for the limited diffusion of ROS and reinforced the antibacterial effect of Indolicidin before its degradation. In vitro, PTBT/I@F127 effectively killed methicillin‐resistant Staphylococcus aureus (MRSA) and E. coli with a remarkable synergy. In diabetic mice and pig models, wound healing rates reached 98% and 83%, respectively, with remarkable angiogenesis and collagen deposition, after receiving PTBT/I@F127. Transcriptomic analysis revealed that Wnt/β‐catenin signaling pathways were involved in promoting tissue regeneration, while inflammation‐associated signaling pathways, such as NF‐κB and IL‐17, were concurrently regulated, thereby alleviating inflammation and reshaping the immune microenvironment in infected wounds. Collectively, this PTBT/Indolicidin‐based thermosensitive hydrogel effectively eliminated resistant bacteria, mitigated inflammation, stimulated angiogenesis, and accelerated healing of infected diabetic wounds, offering a safe, controllable, and translationally promising therapeutic strategy.