An inflammation-responsive hydrogel based on gelatin, loaded with chrysanthemum-derived exosomes, enhances nerve injury repair and mitigates neuropathic pain through the modulation of macrophage polarization.

Peripheral nerve injury (PNI) can result in the loss of motor function and inflammatory pain, particularly in patients with diabetes. In this study, we developed an intelligent hydrogel (GBPVA) that responds to inflammatory stimuli, composed of boric acid-modified gelatin (GelBA) and polyvinyl alcohol (PVA), and loaded with chrysanthemum-derived exosomes (Exos). This hydrogel exhibits inflammation responsiveness. It can rapidly release exosomes within the inflammatory microenvironment, modulate macrophage polarization, and promote the transition of macrophages to the regenerative M2 phenotype, thereby ameliorating the inflammatory response, facilitating neural repair, and alleviating neuropathic pain. In vitro experiments demonstrated that GBPVA/Exos possesses excellent mechanical properties, self-healing capability, strong tissue adhesion (with an adhesion strength to porcine skin of up to 41.92 kPa), and biocompatibility, supporting the adhesion, migration, and axonal growth of both neuronal and Schwann cells. In vivo animal models revealed that this hydrogel significantly inhibits inflammatory responses, promotes the regeneration of nerve fibers and myelin sheaths, improves motor function (with the sciatic functional index (SFI) recovering to -23.8 after 4 weeks of GBPVA/Exos treatment), reduces muscle atrophy, and effectively alleviates diabetes-associated neuropathic pain (After GBPVA/Exos treatment, the paw withdrawal threshold (PWT) in rats increased to approximately 53.1 g, approaching the baseline level (∼55.0 g) observed prior to PNI. Moreover, the thermal withdrawal latency (TWL) increased from 13.4 s to 14.7 s following GBPVA/Exos treatment.). This multifunctional hydrogel integrates natural plant-derived exosomes with intelligent materials, offering a novel strategy for the treatment of diabetic peripheral nerve injury.