A biomimetic supramolecular hydrogel enabling sequential dual-agent release reprograms the inflammatory...

Peripheral nerve injury (PNI) repair is fundamentally hindered by a dysregulated inflammatory microenvironment and insufficient bioactive components. Conventional hydrogels fail to concurrently integrate dynamic responsiveness, neural biomimicry, and inflammation regulation. Herein, we engineered a biomimetic supramolecular hydrogel capable of reprogramming the immune microenvironment. This hydrogel was constructed through the reversible self-assembly of carboxymethyl chitosan (CM-CTS) and oxidized chondroitin sulfate (OCS), enabling the sequential release of a vascular endothelial growth factor mimetic peptide (QK) and dopamine (DA). The hydrogel, designated QK@CM-CTS/OCS-DA, exhibited critical biomaterial properties for neural applications: injectability for minimally invasive delivery, rapid self-healing capability, robust structural stability under dynamic conditions, appropriate mechanical strength matching soft neural tissue, and favorable cytocompatibility. Moreover, in vivo implantation of the hydrogel elicited no discernible inflammatory response, and it underwent near-complete degradation within 6 weeks. Furthermore, the QK@CM-CTS/OCS-DA hydrogel actively reprogrammed the injury site: the initial burst release of the QK peptide potently modulated macrophage polarization toward an anti-inflammatory M2 phenotype and drove early angiogenesis, while the subsequent sustained release of dopamine synergized with the CM-CTS/OCS matrix to promote Schwann cell migration, axonal extension, and myelination. Crucially, the QK@CM-CTS/OCS-DA hydrogel repaired the injured rat sciatic nerve, attenuated gastrocnemius atrophy, and promoted remyelination, restored the conduction function and motor function. While modulating inflammation and immune responses, the QK@CM-CTS/OCS-DA hydrogel also effectively enhanced energy supply, creating favorable microenvironment for peripheral nerve regeneration. Consequently, this study developed a QK@CM-CTS/OCS-DA biomimetic supramolecular hydrogel with sequential delivery functionality and demonstrated its therapeutic potential in PNI repair. STATEMENT OF SIGNIFICANCE: Peripheral nerve injuries are challenging to treat due to harmful inflammation and insufficient bioactive components. Conventional hydrogels fail to concurrently integrate dynamic responsiveness, neural biomimicry, and inflammatory microenvironment reprogramming. Herein, the CM-CTS/OCS matrix employed endows the hydrogel with injectability, self-healing capability, and appropriate mechanical strength, enabling minimally invasive implantation and adaptation to irregular nerve defect cavities while maintaining structural integrity. Through the sequential release of QK peptide and dopamine, the QK@CM-CTS/OCS-DA hydrogel reduces oxidative stress, attenuates early inflammation, guides Schwann cell migration, accelerates axon regrowth, and enhances myelin formation. This study has developed a mechanism-driven biomimetic supramolecular hydrogel, which combines dynamic material design with complex biological effects, providing active substances and an appropriate regenerative microenvironment for peripheral nerve regeneration.