Zhejie Chen,Wei Hao,Caifang Gao,Yangyang Zhou,Chen Zhang,Jinming Zhang,Ruibing Wang,Yitao Wang,Shengpeng Wang
With the development of synthesis technology, modified messenger RNA (mRNA) has emerged as a novel category of therapeutic agents for a broad of diseases. However, effective intracellular delivery of mRNA remains challenging, especially for its sensitivity to enzymatic degradation. Here, we propose a polyphenol-assisted handy delivery strategy for efficient in vivo delivery of IL-10 mRNA. IL-10 mRNA binds to polyphenol ellagic acid through supramolecular binding to yield a negatively charged core, followed by complexing with linear polyetherimide and coating with bilirubin-modified hyaluronic acid to obtain a layer-by-layer nanostructure. The nanostructure specifically up-regulated the level of IL-10, effectively inhibited the expression of inflammatory factors, promoted mucosal repair, protected colonic epithelial cells against apoptosis, and exerted potent therapeutic efficacy in dextran sulfate sodium salt-induced acute and chronic murine models of colitis. The designed delivery system without systemic toxicity has the potential to facilitate the development of a promising platform for mRNA delivery in ulcerative colitis treatment.
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. Graphical abstract
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