Molecular–Cellular Two-Pronged Reprogramming of Inflammatory Soft-Tissue Interface with an Immunosuppressive Pure DNA Hydrogel

Effective modulation of persistent inflammation is crucial for chronic wound healing. However, the interaction cascade between inflammatory factors and immune cells at the soft-tissue wound interface poses an incredible challenge for this purpose. Here, we report an immunosuppressive pure DNA hydrogel (Is-pDNAgel) that reprograms inflammatory responses from both molecular and cellular dimensions. Specifically, high-density negative charges enable Is-pDNAgel to efficiently scavenge free chemokines, mitigating neutrophil and macrophage infiltration. Moreover, its immunosuppressive domain synergistically acts on activated residual immune cells and suppresses multiple proinflammatory signaling pathways, thereby creating a positive circuit to boost anti-inflammatory efficacy. Is-pDNAgel can further facilitate migration and proliferation of endogenous endothelial cells owing to its intrinsic extracellular matrix-mimicking structure, promoting re-epithelialization and neovascularization for tissue regeneration without additional bioactive components. Such an "all-in-one" hydrogel outperforms a commercial dressing to accelerate the healing of chronic wounds in a diabetic mouse model, offering a valuable tool for developing regenerative medicine.