Dual-functional nanotherapeutics: A novel approach to siRNA-mediated TNF-α silencing in inflammatory bowel disease

A novel Eudragit S100-coated and mannose-modified liposome enables colon-specific and macrophage-targeted siRNA delivery. EML/siRNA exhibit excellent stability, biocompatibility, and efficient intracellular delivery siRNA. • The nanocarrier protects TNF-α siRNA from Gastrointestinal (GI) degradation and achieves responsive release in the colon. • Treatment in IBD models significantly downregulates pro-inflammatory cytokines and promotes tissue repair. • The platform provides a targeted and improved therapeutic strategy for precise IBD management. Inflammatory bowel disease (IBD) is a chronic and clinically important intestinal disorder with rapidly rising global incidence and prevalence. While biological therapies targeting tumor necrosis factor-alpha (TNF-α), a key cytokine in IBD pathogenesis, have shown clinical efficacy, their use is often limited by systemic adverse effects. RNA interference (RNAi) offers a promising strategy for precise gene silencing, yet its therapeutic application is constrained by the poor stability and inefficient in vivo delivery of small interfering RNA (siRNA). To overcome these challenges, we developed a macrophage-targeted, colon-specific liposomal system for delivering TNF-α siRNA. The liposomes were functionalized with mannose to selectively engage the mannose receptor (MR, CD206), highly expressed on macrophages, and coated with Eudragit S100 (ES100), a pH-responsive polymer that shields siRNA from gastrointestinal degradation and enables site-specific release in the colon. The resulting ES100-coated, mannose-modified liposomes (EML/siRNA) demonstrated enhanced cellular uptake and efficient siRNA delivery to macrophages both in vitro and in vivo. In animal models of IBD, treatment with EML/siRNA significantly downregulated pro-inflammatory cytokine, alleviated intestinal inflammation, and promoted mucosal tissue repair, as evidenced by histopathological analysis. This study introduces a dual-functional nanotherapeutic platform that combines targeted RNAi-mediated TNF-α silencing with colon-specific delivery and mucosal protection, offering a promising and refined therapeutic strategy for IBD. Download: Download high-res image (159KB) Download: Download full-size image