A self-assembling peptide-based hydrogel containing NF-<i>κ</i>B inhibitors and NGF for peripheral nerve injury repair

An inflammatory response may be initiated after peripheral nerve injury (PNI), potentially hindering the repair and regeneration of damaged nerves. Administering anti-inflammatory agents to modulate macrophage phenotypes may reduce post-injury inflammation and show potential for treating PNI. Regrettably, the limited half-lives of these compounds within the human body constrain their efficacy as anti-inflammatory agents. In this study, we co-assembled picroside II (PII) and nerve growth factor (NGF) with the hydrogelator compound Nap-Phe-Phe-Tyr-OH (NapFFY) to form a supramolecular hydrogel, PII/NGF/NapFFY@Gel, which could be accurately delivered to the nerve injury site via<i>in situ</i>injection to improve its bioavailability. Our results demonstrated that the PII/NGF/NapFFY@Gel exhibits favorable drug slow-release performance in both<i>in vivo</i>and<i>in vitro</i>experiments. Furthermore, cell and animal studies revealed that the PII/NGF/NapFFY@Gel effectively enhanced nerve recovery and regeneration by modulating the inflammatory microenvironment. This mechanism involves inhibiting the NF-<i>κ</i>B inflammatory signaling pathway, suppressing macrophage polarization to the M1 phenotype, and upregulating the expression of proteins associated with nerve regeneration. Taken together, the results of this study suggest that improving the inflammatory microenvironment and promoting nerve repair through the<i>in situ</i>injection of PII/NGF/NapFFY@Gel with sustained drug release may be a novel treatment for PNI.