Carboxymethyl Cellulose-Collagen XVII Composite Hydrogel Reprograms the Immune-Oxidative Microenvironment for Enhanced Skin Wound Repair

Abstract

Chronic or non-healing wounds remain a major clinical challenge, driven by sustained inflammation and an unfavorable repair microenvironment. Type XVII collagen (COL17) is a key hemidesmosomal protein essential for keratinocyte adhesion and epidermal homeostasis. Nevertheless, whether exogenous COL17 can be harnessed as a therapeutic cue in otherwise conventional wounds remains unclear. Here, we combined COL17 with sodium carboxymethyl cellulose (CMC), a clinically familiar polysaccharide, to construct a composite hydrogel and examine its role in cutaneous repair. The CMC/COL17 hydrogels featured a uniform, extracellular matrix (ECM)like porous network and showed COL17 dose-dependent viscoelastic enhancement, enabling them to form coatings that spread easily yet retain position on the wound. COL17 showed no cytotoxicity to fibroblasts across a wide concentration range and significantly enhanced their migration in vitro. In a murine full-thickness dorsal wound model, topical CMC/COL17 application accelerated wound closure, yielded a thicker and more continuous neoepidermis, improved collagen organization, and induced the early appearance of hair follicle-like structures. RNA sequencing of wound tissue showed suppression of inflammation-and chemotaxis-related pathways, including IL-17 and TNF signaling, with concurrent enrichment of cell-matrix interaction, cytoskeleton, and tissue development pathways. Consistently, at the cellular level, COL17 polarized macrophages toward an M2-like phenotype, suppressed proinflammatory cytokine expression, and reduced intracellular reactive oxygen species (ROS) in both fibroblasts and macrophages. Collectively, these results indicate that a simple CMC/COL17 hydrogel can couple a widely used cellulose carrier with a nicherelevant ECM protein to provide both anti-inflammatory and pro-regenerative effects, thus positioning COL17 as an active regulator in wound repair instead of solely a structural basement membrane component.