Ginsenoside Rd-functionalized hydrogel for immune modulation and enhanced diabetic wound healing.

Abstract

Persistent inflammation and oxidative stress are central barriers to effective diabetic wound repair. Successful healing requires restoration of a coordinated local microenvironment, yet achieving this remains a major clinical challenge. Herein, a composite ginsenoside Rd-functionalized hydrogel (Gel@Rd) with dynamic and static dual networks was fabricated using extracellular matrix-mimicking biomaterials. Gel@Rd exhibited favorable biocompatibility, self-healing capacity, and mechanical stability, facilitating prolonged retention and release of Rd at the wound site. In diabetic wounds, Gel@Rd attenuated oxidative stress and inflammatory signaling, promoted angiogenesis and collagen deposition, and reshaped a regeneration-favorable immune microenvironment by driving macrophage polarization toward the reparative M2-like phenotype. Transcriptomic and proteomic analyses indicated that Rd exerted inflammation-regulatory effects potentially via modulating the TLR4-NF-κB cascade and the TNF-α signaling pathway, and also participated in regulating pathways associated with metabolism and tissue repair. These multifaceted effects translated into accelerated wound closure and improved tissue regeneration in diabetic mice. Collectively, this work establishes an integrated natural product-based hydrogel platform for diabetic wound therapy and provides a rational strategy for combining sustained drug delivery with microenvironmental reprogramming to enhance healing.