• CXCR5-engineered MSCs (MSCCXCR5) exhibit enhanced homing to splenic CXCL13-rich B-cell zones, improving targeted delivery to sites of immune dysregulation.
• MSCCXCR5 therapy significantly reduces sepsis-induced lymphopenia and preserves follicular and germinal center B-cell populations, restoring humoral immunity.
• Treatment with MSCCXCR5 confers dual-phase protection in a CLP mouse model, improving survival during both the hyperinflammatory and immunosuppressive phases of sepsis.
• This engineered MSC approach offers a promising strategy to prevent secondary infections and mitigate post-sepsis syndrome, addressing a critical unmet clinical need.