Bioactive Chemically Modified Silk Fibroin Accelerates Wound Healing via the Regulation of Macrophage Polarization

The programmed polarization of macrophages, which exhibit remarkable plasticity from pro-inflammatory (M1) to anti-inflammatory (M2) phenotypes, serves as a key driver of skin wound healing. However, dysregulated macrophage polarization toward a dominant M1 phenotype can induce excessive inflammation and hinder wound healing. Current therapeutic strategies to promote M2 polarization, such as cytokines, anti-inflammatory drugs, and stem cell therapies, have limited effectiveness, complex manufacturing processes, and potential toxicity. Here, we report the development of mannose- and sulfonic acid-modified silk fibroin (SF) that are bioactive and promote M2 polarization by activating the MR-ERK/STAT6 signaling axis. In vitro studies showed increased expression of CD206 and anti-inflammatory gene markers, confirming their ability to regulate macrophage polarization without additional therapeutic agents. Moreover, the mannose- and sulfonic acid-modified SF films, used as wound dressings, enhanced wound healing by promoting M2 macrophage polarization, angiogenesis, collagen deposition, and wound closure. These findings highlight the potential of chemically modified SF as bioactive materials for immune modulation and tissue regeneration.