A cyclic heptapeptide-based hydrogel boosts the healing of chronic skin wounds in diabetic mice and patients

Abstract The combined use of peptides, nanomaterials, and hydrogels is a promising strategy for chronic skin wound healing, which remains a huge clinical challenge. Here, we optimized the RL-QN15 peptide, which was shown to be a pro-healing drug candidate in our previous research, to obtain the cyclic heptapeptide (Cy RL-QN15 ) with considerable therapeutic potency against skin wounds. Furthermore, a Zn 2+ -crosslinked sodium alginate (ZA) hydrogel containing hollow polydopamine (HPDA) nanoparticles loaded with Cy RL-QN15 (HPDAlCy RL-QN15 /ZA hydrogel) was prepared and characterized, which significantly enhanced the pro-healing potency of Cy RL-QN15 . At the cellular level, this nontoxic hydrogel accelerated the proliferation, migration, tube formation, and scratch healing of skin cells, regulated the secretion of cytokines from macrophages, directly scavenged free radicals, and decreased reactive oxygen species. Moreover, the HPDAlCy RL-QN15 /ZA hydrogel significantly accelerated the healing of full-thickness skin wounds in type 2 diabetic mice by promoting the transition of macrophages to the M2 phenotype to reduce inflammation and cause re-epithelialization, formation of granulation tissue, deposition of collagen, and angiogenesis. Of note, the hydrogel also facilitated wound healing of diabetic patient skin cultured ex vivo. Overall, the HPDAlCy RL-QN15 /ZA hydrogel presents a novel therapeutic strategy for clinical chronic skin wound (diabetic ulcer) healing.