<p>Dysregulated immune responses and excessive inflammation are central drivers of early sepsis progression. Interleukin-10 (IL-10) is a key anti-inflammatory cytokine. However, the therapeutic potential and mechanistic basis of IL-10 mRNA delivery in correcting early immune dysfunction during sepsis remain poorly defined. In this study, we developed a mannose-modified mesoporous silica nanoparticle system (MMP/IL-10 mRNA) to stabilize IL-10 mRNA and enable sustained release for the immunoregulatory treatment of sepsis. The nanoparticles exhibited uniform size, structural stability, efficient mRNA protection, and sustained IL-10 expression. In LPS-stimulated macrophages, MMP/IL-10 mRNA enhanced cell viability, promoted M2 polarization, suppressed pro-inflammatory cytokine production (TNF-α, IL-1β, IL-6, and IL-17A), and restored the IL-10/IL-17A balance. In a cecal ligation and puncture–induced murine sepsis model, MMP/IL-10 mRNA improved 7-day survival, enhanced bacterial clearance, alleviated lung and liver injury, and ameliorated systemic inflammatory imbalance. Mechanistically, treatment reduced TLR4 expression, prevented IκBα degradation, inhibited NF-κB p65 phosphorylation, and upregulated endogenous IL-10 and DEL-1. Importantly, no detectable toxicity or organ damage was observed. These findings demonstrate that MMP/IL-10 mRNA enables efficient, sustained, and safe delivery of IL-10 mRNA, attenuates early hyper-inflammation, and improves immune dysregulation in sepsis, highlighting its potential as a promising immunoregulatory therapeutic strategy.</p> Graphical abstract <p></p>