SOCS3-siRNA-loaded exosomes derived from adipose mesenchymal stem cells promote spinal cord injury recovery through the synergy between PTEN/PI3K/AKT/mTOR and JAK2/STAT3

Spinal cord injury (SCI) recovery is hindered by limited neural regeneration and a persistent inflammatory microenvironment. Here, we developed a novel therapeutic strategy using adipose-derived stem cell exosomes (ADSC-Exos) engineered to deliver SOCS3-siRNA (S-Exos). We first identified an intrinsic mechanism where native ADSC-Exos suppress the regenerative inhibitor PTEN via their endogenous miR-10b-5p. By loading these exosomes with SOCS3-siRNA, we achieved a dual-inhibition strategy targeting both key negative regulators of neural repair. In vitro, S-Exos stimulated neurite outgrowth and were readily internalized by neurons and microglia/macrophages. When administered intrathecally to SCI mouse models, S-Exos markedly improved motor function, reduced spinal cord lesion pathology, enhanced nerve regeneration, and decreased apoptosis. Crucially, the treatment remodeled the neuroinflammatory microenvironment by promoting a phenotypic switch in microglia/macrophages from a pro-inflammatory M1 to an anti-inflammatory M2 state. Mechanistically, these effects were driven by the synergistic activation of the PI3K/AKT/mTOR and JAK2/STAT3 signaling pathways. Our findings establish these engineered exosomes as a potent and translatable therapy for SCI, promoting robust neural repair and functional recovery by concurrently targeting key regenerative and inflammatory pathways. © 2026 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.