Anti-inflammation lipid nanoparticles enable localized mRNA therapy for inflammatory bowel disease

Inflammatory bowel disease (IBD) is an incurable disorder that requires long-term management, which is limited by suboptimal efficacy and systemic toxicity of current treatments. We developed a series of glucocorticoid-derived ionizable lipids and formulated them into lipid nanoparticles (LNPs) for rectal and lesion-localized mRNA delivery. MP2 LNPs, the lead formulation based on a methylprednisolone-derived ionizable lipid, showed a 15-fold higher delivery efficiency in vivo than the FDA approved SM102 LNPs. When loaded with interleukin-35 (IL-35) mRNA, MP2 LNPs (MP2-IL-35) ameliorated colitis in acute and chronic IBD mouse models, as shown by improved clinical scores, preserved colon length, and reduced pro-inflammatory cytokines. In ex vivo human colonic biopsies, MP2 LNPs enabled effective mRNA delivery in immune, epithelial and endothelial cells. Moreover, in biopsies from patients with IBD, MP2-IL-35 LNPs significantly reshaped effector and regulatory T cell subsets. Together, these findings support MP2-IL-35 LNPs as a promising mRNA therapy for IBD.