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

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 (CYRL-QN15) with considerable therapeutic potency against skin wounds. Furthermore, a Zn²⁺-crosslinked sodium alginate (ZA) hydrogel containing hollow polydopamine (HPDA) nanoparticles loaded with CYRL-QN15 (HPDA/CYRL-QN15/ZA hydrogel) was prepared and characterized, which significantly enhanced the pro-healing potency of CYRL-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 HPDA/CYRL-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 reparative M2 phenotype to restore inflammation, boost re-epithelialization, promotion of granulation tissue, deposition of collagen, and angiogenesis. Of note, the hydrogel also facilitated wound healing in diabetic skin ulcer in vivo. Overall, the HPDA/CYRL-QN15/ZA hydrogel represents a novel therapeutic strategy for chronic skin wound (diabetic ulcer) healing.