RPS3‐Enriched Extracellular Vesicles Mediate Liver‐Spinal Cord Inter‐Organ Communication

Spinal cord injury activates the liver to send extracellular vesicles loaded with RPS3 protein to the lesion site. These vesicles are taken up by neural stem cells and astrocytes, triggering NF‐κB signaling, impairing the regeneration of neurons and myelin, and promotes harmful inflammation, ultimately hindering recovery. Blocking this liver‐spinal cord communication pathway presents a promising therapeutic strategy. ABSTRACT Spinal cord injury (SCI) induces bidirectional inter‐organ communication via extracellular vesicles (EVs) with multiple peripheral organs. Here, we identify the liver as a critical regulator that inhibits endogenous neuronal repair. Proteomics of plasma EVs from SCI patients and RNA‐sequence of post‐injury livers revealed a rapid increase of ribosomal protein S3 (RPS3) in plasma EVs and liver‐derived EVs (LEVs). These RPS3‐enriched 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‐light‐chain‐enhancer of activated B cells (NF‐κB) 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‐hepatic cascade that further amplified RPS3 expression in hepatocytes. Crucially, in vivo depletion of KCs or hepatic RPS3 effectively attenuated NF‐κB activation, restored axonal regeneration and remyelination, and promoted neurological functional recovery. This work highlights a liver‐spinal cord axis wherein RPS3‐enriched hepatic KC‐derived EVs impair central nervous system (CNS) regeneration via the NF‐κB activation, presenting a promising prognostic biomarker and novel therapeutic target for SCI. Spinal cord injury activates the liver to send extracellular vesicles loaded with RPS3 protein to the lesion site. These vesicles are taken up by neural stem cells and astrocytes, triggering NF-κB signaling, impairing the regeneration of neurons and myelin, and promotes harmful inflammation, ultimately hindering recovery. Blocking this liver-spinal cord communication pathway presents a promising therapeutic strategy. ABSTRACT Spinal cord injury (SCI) induces bidirectional inter-organ communication via extracellular vesicles (EVs) with multiple peripheral organs. Here, we identify the liver as a critical regulator that inhibits endogenous neuronal repair. Proteomics of plasma EVs from SCI patients and RNA-sequence of post-injury livers revealed a rapid increase of ribosomal protein S3 (RPS3) in plasma EVs and liver-derived EVs (LEVs). These RPS3-enriched 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-light-chain-enhancer of activated B cells (NF-κB) 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-hepatic cascade that further amplified RPS3 expression in hepatocytes. Crucially, in vivo depletion of KCs or hepatic RPS3 effectively attenuated NF-κB activation, restored axonal regeneration and remyelination, and promoted neurological functional recovery. This work highlights a liver-spinal cord axis wherein RPS3-enriched hepatic KC-derived EVs impair central nervous system (CNS) regeneration via the NF-κB activation, presenting a promising prognostic biomarker and novel therapeutic target for SCI. Advanced Science, EarlyView.