Exosomes target liver TREM-1 to break the systemic inflammatory cascade and improve spinal cord injury outcomes.

Background: Spinal cord injury (SCI) is a catastrophic neurological disorder characterized by irreversible functional deficits and the absence of effective clinical therapies. Increasing evidence suggests liver inflammation has emerged as a critical contributor to the exacerbation of secondary injury by amplifying systemic inflammatory responses and hindering neurological recovery following SCI, suggesting that mitigating hepatic inflammation may alleviate disease progression. Recently, exosomes have gained attention as promising therapeutic agents due to their ability to mediate intercellular communication and deliver bioactive molecules. Whether exosome-based interventions can modulate liver inflammation and improve SCI outcomes remains to be elucidated. Methods: Functional recovery was assessed using BMS, gait analysis and inclined plane test. Histological and molecular analyses were performed to evaluate spinal cord pathology. Downstream inflammatory signaling pathways were further analyzed through immunohistology staining, flow cytometry and q-RT-PCR to elucidate the cascade involved in liver-mediated secondary injury. Exosomal cargo was characterized by proteomics and western blotting with a focus on heat shock protein 70 (HSP70). Competitive inhibition experiment was used to determine the interaction between exosome-delivered HSP70 and Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) on hepatic macrophages Results: Exosomes from different sources significantly improve functional recovery following SCI, as evidenced by enhanced locomotor performance and reduced tissue damage. Importantly, exosome treatment markedly attenuated liver inflammation, characterized by reduced macrophage activation and decreased expression of pro-inflammatory cytokines. Mechanistically, we found that exosomal HSP70 interacts with TREM-1 on hepatic macrophages. This interaction competitively inhibits the binding of HMGB1, a key damage-associated molecular pattern that is persistently elevated after SCI. By blocking the HMGB1-TREM-1 axis, exosomal HSP70 effectively suppresses downstream inflammatory signaling and mitigates the amplification of systemic inflammation originating from the liver. Conclusion: This study uncovers a previously unrecognized systemic mechanism by which exosomes promote recovery after SCI through the modulation of liver inflammation. By targeting the HMGB1-TREM-1 signaling pathway in hepatic macrophages via exosomal HSP70 delivery, exosomes effectively suppress the inflammatory cascade that contributes to secondary injury. The translational potential of this article: Targeting systemic inflammation, particularly liver-mediated immune responses, may complement existing neuroprotective strategies and improve therapeutic outcomes. These findings pave the way for future preclinical and clinical studies aimed at developing exosome-based interventions for SCI and other neuroinflammatory disorders.