Programmable DNA‐Peptide Conjugated Hydrogel via Click Chemistry for Sequential Modulation of Peripheral Nerve Regeneration

Abstract During peripheral nerve regeneration, current deoxyribonucleic acid (DNA)‐based therapeutic platforms face the challenge of precisely regulating Schwann cells (SCs) fate to sustain their repair phenotype due to their inability to stably and precisely integrate multiple bioactive components. Herein, the strain‐promoted azide–alkyne cycloaddition reaction is utilized to integrate the neurotrophic factor mimetic peptide RGI and the laminin‐derived peptide IKVAV into DNA monomers. Through DNA sequence self‐assembly, a programmable DNA‐peptide conjugated hydrogel is constructed for loading bone marrow mesenchymal stem cell‐derived exosomes. This programmable hydrogel can rapidly, stably, and precisely integrate various bioactive components into the hydrogel network, thereby enabling sequential modulation of peripheral nerve repair. In vitro, studies show that this hydrogel, through sequential modulation mechanisms, can activate the neuregulin‐1 (Nrg1)/ErbB pathway to induce the reprogramming of SCs and promote the recruitment and proliferation of repair SCs. The induced repair SCs promote neuronal axon outgrowth and enhance tube formation in endothelial cells. In vivo, this programmable hydrogel can gelate in situ through intraneural injection in a rat sciatic nerve crush injury model, promoting nerve regeneration and functional recovery. In summary, this work provides an effective and practical strategy for peripheral nerve regeneration.