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Here, we identify the liver as a critical regulator that inhibits endogenous neuronal repair. Proteomics of plasma EVs from SCI patients and RNA\u2010sequence of post\u2010injury livers revealed a rapid increase of ribosomal protein S3 (RPS3) in plasma EVs and liver\u2010derived EVs (LEVs). These RPS3\u2010enriched LEVs are transported to the spinal cord lesion sites, where they are taken up by neural stem cells (NSCs) and astrocytes. Mechanistically, RPS3 activates nuclear factor kappa\u2010light\u2010chain\u2010enhancer of activated B cells (NF\u2010\u03baB) signaling in recipient cells, inhibiting NSC differentiation into neurons and oligodendrocytes and polarizing astrocytes toward a neuroinflammatory phenotype. Further detection identified activated Kupffer cells (KCs) as the primary source of RPS3, initiating an intra\u2010hepatic cascade that further amplified RPS3 expression in hepatocytes. Crucially, in vivo depletion of KCs or hepatic RPS3 effectively attenuated NF\u2010\u03baB activation, restored axonal regeneration and remyelination, and promoted neurological functional recovery. This work highlights a liver\u2010spinal cord axis wherein RPS3\u2010enriched hepatic KC\u2010derived EVs impair central nervous system (CNS) regeneration via the NF\u2010\u03baB activation, presenting a promising prognostic biomarker and novel therapeutic target for SCI.<\/jats:p>","DOI":"10.1002\/advs.202517019","type":"journal-article","created":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T05:27:01Z","timestamp":1768022821000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["RPS3\u2010Enriched Extracellular Vesicles Mediate Liver\u2010Spinal Cord Inter\u2010Organ Communication"],"prefix":"10.1002","volume":"13","author":[{"given":"Peiwen","family":"Song","sequence":"first","affiliation":[{"name":"Department of Orthopedics (Spinal Surgery) The First Affiliated Hospital of Anhui Medical University Laboratory of Spinal and Spinal Cord Injury Regeneration and Repair The First Affiliated Hospital of Anhui 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