Exercise-derived exosomal miR-151-3p: An innovative anti-inflammatory and antioxidant therapeutic for spinal cord injury

Exercise (Exe) training is a cornerstone of multimodal rehabilitation of patients with spinal cord injury (SCI), yet the precise mechanisms through which it exerts its therapeutic benefits remain unclear. Exosomes (Exos) are key mediators of intercellular communication and promising vehicles for targeted therapy. This study aimed to investigate the function and underlying mechanism of exercise-derived exosomes (Exe-Exos) in SCI recovery. Circulating Exos were isolated from rats subjected to a 4-week treadmill Exe regimen and from sedentary controls. A gelatin methacrylate (GelMA) hydrogel microneedles (Hyd MNs) system was developed for the targeted, sustained delivery of these Exos directly to the injury epicenter at the T10 spinal segment in a rat SCI model. Using integrated in vitro and in vivo approaches, we showed that Exe-Exos significantly promoted motor function recovery, attenuated tissue damage, reduced apoptosis, and alleviated both inflammation and oxidative stress (Oxs) after SCI. Small RNA sequencing revealed that miR-151-3p is a key functional cargo that is enriched in Exe-Exos. Gain- and loss-of-function studies revealed that exosomal miR-151-3p exerts its protective effects by directly targeting the mitochondrial membrane protein ROMO1. This targeting led to the coordinated inhibition of the pro-apoptotic JNK/Caspase pathway, suppression of the NF-κB-mediated inflammatory cascade, and activation of the Nrf2/HO-1 antioxidant axis. Collectively, our findings establish Exe-Exos, specifically exosomal miR-151-3p, as an exercise-responsive circulating signaling axis that orchestrates multifaceted protection against secondary injury after SCI, offering an innovative, mechanism-based strategy for neuroregenerative therapy.