Maleimide-Modified PEG-PLGA Nanoparticles Facilitate Gut Immune Tolerance via siCD40 Delivery to Dendritic Cells for the Treatment of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is characterized by chronic inflammation, driven by immune dysregulation. One of the key contributors to this persistent inflammation is the dysregulation of dendritic cells (DCs) in the gut and mesenteric lymph nodes (MLNs), particularly through CD40 signaling, which plays a central role in modulating immune responses. Targeting CD40 in DCs therefore represents a promising approach for restoring immune balance and improving IBD. In this study, we developed maleimide (Mal)-modified PEG-PLGA nanoparticles for the targeted delivery of siCD40 to DCs in the gut and MLNs. In a TNBS-induced colitis mouse model, Mal-modified siCD40 nanoparticles significantly alleviated intestinal inflammation, improved colonic histopathology, and induced a marked increase in regulatory T cells (Tregs) within the gut and MLNs, promoting immune tolerance while preserving gut microbiota composition. Furthermore, Mal-modified nanoparticles effectively improved gut inflammation and maintained immune tolerance even at low doses. Our findings suggest that Mal-modified PEG-PLGA nanoparticles offer a promising strategy for targeted IBD treatment by modulating local immune responses, restoring immune tolerance, and maintaining gut homeostasis. Moreover, this nanoparticle-based localized and precise immune modulation approach may provide valuable insights into the treatment of organ-specific immune-mediated diseases.