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 (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 (HPDAlCyRL-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 HPDAlCyRL-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 HPDAlCyRL-QN15/ZA hydrogel presents a novel therapeutic strategy for clinical chronic skin wound (diabetic ulcer) healing.

Peptide RL‐QN15 promotes regeneration of epidermal nerve fibers and recovery of sensory function in diabetic skin wounds

“…An experimental model of type 2 diabetes mellitus (T2DM) was established in C57BL/6 mice ( n = 38) using a high‐fat diet and multiple low‐dose injections of streptozotocin (STZ). In brief, after 4 weeks of a high‐fat diet, mice were weighed (25–30 g), then injected intraperitoneally with STZ (Sigma‐Aldrich, MO, USA) at 30 mg/kg for six consecutive days after overnight fasting 20 . In SD rats ( n = 22), T2DM was induced by a combination of high‐fat diet and intraperitoneal injection of STZ.…”

“…In brief, after 4 weeks of a high-fat diet, mice were weighed (25-30 g), then injected intraperitoneally with STZ (Sigma-Aldrich, MO, USA) at 30 mg/ kg for six consecutive days after overnight fasting. 20 In SD rats (n = 22), T2DM was induced by a combination of high-fat diet and intraperitoneal injection of STZ. In brief, rats were housed alone in plastic cages and fed a high-fat diet for four weeks, followed by intraperitoneal injection of STZ (50 mg/kg) for two consecutive days after overnight fasting to induce T2DM.…”

“…Epidermal repair-promoting peptides extracted from amphibian skin secretions have attracted increasing attention in recent years. [19][20][21][22][23] We previously showed that the peptide RL-QN15 exhibits excellent pro-healing effects on full-thickness skin wounds in swine, oral ulcers in rats, and full-thickness dorsal skin wounds in mice, highlighting its potential as a promising candidate for the development of new therapeutics against skin wounds. 13,24,25 However, whether RL-QN15 can promote peripheral nerve regeneration and sensory function recovery in wounds after repair remains unknown.…”

Hydrogel Loaded with Peptide-Containing Nanocomplexes: Symphonic Cooperation of Photothermal Antimicrobial Nanoparticles and Prohealing Peptides for the Treatment of Infected Wounds

“…These findings suggest that the MNPs/Cy RL-QN15 /FeCMCS hydrogel holds potential as an innovative agent for promoting wound healing. This potential stems from multiple advantageous properties, including the efficacy of the Cy RL-QN15 peptide in wound healing enhancement, 28 encapsulation and photothermal bactericidal activity of MNPs, and porous architecture of the hydrogel, allowing for the homogeneous dispersion of the physical characteristics of MNPs. In vivo and in vitro investigations demonstrated that the MNPs/Cy RL-QN15 / FeCMCS hydrogel facilitated the regeneration and remodeling of chronically infected wounds by efficiently eliminating both Gram-positive and Gram-negative bacteria, enhancing keratinocyte proliferation and migration, and expediting reepithelialization and collagen deposition.…”

“…32 The loading rate and slow-release rate were measured according to previous studies. 25,28 The rheological characteristics of the MNPs/ Cy RL-QN15 /FeCMCS hydrogel, with or without NIR, were analyzed using a rheometer (Anton Paar MCR 302, Austria). Frequency sweep measurements were conducted at 25 °C with a fixed strain of 0.5%.…”