Damage Microenvironment Guided Responsive Smart Hydrogel Design for Self‐Regenerative Repair in Chronic Wound Healing

Abstract Chronic non‐healing wounds, exacerbated by aging, diabetes, and other factors, severely compromise patients' quality of life and impose substantial socioeconomic burdens, thus emerging as a critical public health challenge. Conventional strategies focusing on single‐component modification or simple delivery systems fail to address the complex interplay among growth factor delivery, microenvironmental responsiveness, and tissue repair. Here, single‐cell RNA sequencing (scRNA‐seq) mapped matrix metalloproteinase (MMP) dynamics during healing, guiding therapeutic design. A multifunctional glutathione‐modified hydrogel (GCDGTV) is developed, composed of gelatin, dopamine‐grafted carboxymethyl chitosan, and an MMP‐responsive VEGF fusion protein. GCDGTV features two key innovations: glutathione's thiol chemistry enables precise loading and controlled release of VEGF, while the specific expression of MMPs in the wound microenvironment triggers on‐demand VEGF release, dynamically aligning growth factor delivery with the healing process. Additionally, GCDGTV exhibits tissue‐matched mechanical properties, as well as antioxidant and antibacterial functions. In a rat skin injury model, GCDGTV demonstrated remarkable therapeutic efficacy, significantly accelerating wound closure, promoting angiogenesis, and enhancing collagen deposition. Compared with traditional approaches, GCDGTV offers an integrated system that simultaneously optimizes mechanical support, bioactive molecule delivery, and microenvironmental responsiveness, offering a promising strategy for chronic wound treatment and paving the way for the precision‐driven development of regenerative medicine.