Exosomal Rspondin3 serves as a master regulator of immunometabolic repair in sepsis: synergistic activation of macrophage M2 polarization and endothelial BMP10 signaling.

Sepsis-induced acute lung injury (ALI) involves complex crosstalk between immune and vascular cells, yet therapeutic strategies remain limited. Here, we identify Rspondin3 (Rspo3) as the critical mediator in endothelial progenitor cell-derived exosomes (EPC-Exo) that coordinately regulates macrophage M2 polarization (via Wnt/β-catenin) and endothelial repair (via BMP10/ACVRL1). Using LPS-induced sepsis models combined with single-cell RNA sequencing and metabolomics, we demonstrate that Rspo3-enriched EPC-Exo simultaneously: (i) promote macrophage M2 polarization by enhancing Wnt/β-catenin/TCF4 signaling, and (ii) activate BMP10/ACVRL1-dependent endothelial migration, proliferation and glycolytic homeostasis. Genetic and pharmacological inhibition of Rspo3 or Wnt signaling abolished exosome-mediated immunomodulation, while BMP10 knockdown impaired endothelial functional recovery. In vivo, EPC-Exo administration attenuated pulmonary inflammation, reduced TNF-α/IL-6, increased IL-10/VE-cadherin expression, and restored lung histology-effects reversed by Rspo3 blockade. Mechanistically, EPC-Exo restored dysregulated immunometabolic networks, particularly glycolytic flux in endothelial cells. Our work unveils Rspo3 as a master regulator of the macrophage-endothelial axis in sepsis, providing a molecular blueprint for exosome-based therapies targeting multi-organ dysfunction.