An endoplasmic reticulum stress-responsive nanocomposite hydrogel for diabetic wound healing through a fibroblast-immune cell dual regulation hub

作者：Shaoying Gao, Tao Chen, Chengliang Deng, Gang Liu, Zairong Wei · 发表于：Journal of Nanobiotechnology · 年份：2025 · DOI：10.1186/s12951-025-03732-0 · 被引用次数：6 · 研究领域：Wound Healing and Treatments、Tissue Engineering and Regenerative Medicine、Electrospun Nanofibers in Biomedical Applications

Abstract Diabetic wounds exhibit excessive endoplasmic reticulum stress (ERS), which can lead to fibroblast dysfunction, abnormal natural killer (NK) cell activation, and imbalanced macrophage polarization. ERS exerts a bidirectional regulatory effect on wound fibroblasts and immune cells; simply inhibiting ERS impedes wound tissue regeneration. Existing hydrogels cannot precisely regulate ERS and synergistically repair multicell functional defects. Monocyte Chemoattractant Protein-1 (MCP-1), synthesized by fibroblasts in diabetic wounds, is a key molecular regulator of ERS and fibroblast function and a hub for fibroblast-immune cell interactions. This study constructed histidine–chitosan–fibroblast growth factor receptor (FGFR) agonist peptide 1 (FAP1)–pGPU6/GFP/Neo MCP-1–shRNA plasmid (HCFD) nanoparticles. The HCFD nanoparticles were loaded onto 3-carboxyphenylboronic acid (PBA)-modified methyl acrylate gelatin (GelMA) hydrogel (GP), forming the nanocomposite hydrogel Gel–PBA–HCFD (GPHCFD). The GPHCFD nanocomposite hydrogel utilizes FAP1 to target FGFR on wound fibroblasts. Under conditions of excessive ERS, GPHCFD nanocomposite hydrogels were triggered to break boric acid bonds and protonate histidine imidazole, thereby achieving the precise release of the plasmid, which could stably knock out the MCP-1 gene in fibroblasts. Notably, GPHCFD exhibited excellent ERS-responsive functionality, significantly reducing MCP-1 expression and alleviating excessive ERS in fibroblasts ...