pH-responsive hydrogel delivery of Lycium barbarum glycopeptide coordinates immune-matrix crosstalk to enhance wound healing

Abstract

Advanced wound dressings should combine physical protection with localized and microenvironment-responsive delivery of therapeutic agents. Lycium barbarum glycopeptide (LbGp), a naturally derived macromolecular preparation with reported immunomodulatory and tissue-protective activities; however, its topical use is limited by rapid diffusion and insufficient local retention. Here, we engineered an injectable oxidized sodium alginate/gelatin hydrogel (OSA/Gel@LbGp) for localized delivery of LbGp through dynamic Schiff-base crosslinking. OSA/Gel@LbGp showed favorable cytocompatibility, promoted HaCaT keratinocyte migration, and shifted LPS-challenged macrophages toward a repair-associated phenotype, as evidenced by reduced CD68, TNF-α, and IL-1β and increased CD206, ARG-1, and TGF-β1. In a murine 5-mm full-thickness excisional wound model, OSA/Gel@LbGp accelerated wound closure, reduced granulation-tissue gaps, enhanced re-epithelialization, and improved dermal organization and collagen deposition. RNA sequencing subsequently identified 2,097 upregulated and 980 downregulated genes, revealing an ECM-centered reparative program enriched in ECM–receptor interaction, cell–matrix adhesion, and matrix-remodeling pathways, with Mmp11 emerging as a representative remodeling-associated gene. Consistent with this transcriptional findings, treated wound tissues exhibited increased collagen I/COL1A1, MMP11, and VEGF signals,and reduced inflammation-linked MMP9. Collectively, OSA/Gel@LbGp promoted wound repair by coordinating early immune modulation with subsequent ECM reconstruction. These findings establish a delivery-centered strategy for translating natural macromolecular bioactives into advanced wound dressings that improve both healing kinetics and tissue-repair quality.