Proteolysis-Targeting Chimera-Loaded Hydrogel Dressings Orchestrate Immunoregulation and Angiogenesis to Promote...

The delayed healing of diabetic wounds is primarily attributed to a persistent excessive inflammatory microenvironment and impaired angiogenesis. Here, we identify the STimulator of INterferon Genes (STING) as a key regulator driving this pathological state within the wound milieu. To address this, we developed SD-Gel, a thermosensitive protein-degrading hydrogel loaded with a PROteolysis-TArgeting Chimera (PROTAC) designed for targeted STING degradation. This SD-Gel is characterized by its reactive oxygen species (ROS)-responsive degradation, which enables simultaneous ROS scavenging and controlled PROTAC release. Both in vitro and in vivo studies demonstrated that SD-Gel effectively downregulates STING expression in the mouse monocyte macrophage leukemia cell line (RAW 264.7) and human umbilical vein endothelial cells (HUVECs), rectifying the inflammatory microenvironment and promoting angiogenesis. Consequently, SD-Gel enhanced wound healing by approximately 1.8-fold in a murine model of large-area diabetic wounds. Bulk RNA sequencing of whole skin tissue coupled with bioinformatic reanalysis of the microarray dataset (GSE20966) revealed that STING degradation simultaneously regulates two pivotal phases of wound healing: suppression of inflammation and activation of angiogenesis, thereby establishing a synergistic therapeutic pathway. This immune-coordinated regenerative strategy provides an integrated and effective approach for the treatment of chronic wounds. STATEMENT OF SIGNIFICANCE: The delayed healing of diabetic wounds is primarily attributed to a persistent excessive inflammatory microenvironment and impaired angiogenesis. In this study, we identify sustained STING hyperactivation as a central driver of the chronic inflammatory state in diabetic wounds, promoting excessive secretion of cytokines such as TNF-α and IL-6 and thereby impeding tissue repair. We engineered SD-Gel, a thermosensitive, protein-degrading hydrogel composed of a dual-crosslinked N-isopropylacrylamide/alginate network that provides robust tissue adhesion and biomechanically assisted wound contraction. SD-Gel incorporates a STING-targeting PROTAC and integrates a ROS-responsive module that simultaneously scavenges reactive oxygen species and triggers controlled PROTAC release, ensuring precise and timely STING degradation within the wound niche. In a murine model of large diabetic wounds, SD-Gel effectively suppressed excessive inflammation, restored angiogenic capacity, and markedly accelerated tissue regeneration. This integrative immunoregulatory and pro-angiogenic strategy highlights a promising therapeutic avenue for chronic wound management.