Ginsenoside-Engineered Lipid Nanoparticles in Microbeads Enable Oral siRNA Delivery and Targeted Therapy for Ulcerative Colitis

Small interfering RNAs (siRNAs) have emerged as promising therapeutics for ulcerative colitis (UC) owing to their potent anti-inflammatory effects and favorable biocompatibility. However, effective oral siRNA delivery remains challenging due to limited inflammatory cell targeting, inefficient endosomal escape, and rapid degradation in the gastrointestinal tract. To overcome these barriers, we developed a nano-in-micro modular microbead system for colon-targeted delivery of siRNA against tumor necrosis factor-α (TNF-α). This platform integrates two key components: (i) a library of ginsenoside-based lipid nanoparticles (LNPs) generated by screening natural sterol analogues, among which ginsenoside Rg3-based LNPs (Rg3@siTNF-α) were identified as optimal carriers, enabling enhanced macrophage targeting via glucose transporter-1–mediated recognition and promoting endosomal escape by attenuating Niemann–Pick C1 (NPC1)–dependent recycling; and (ii) a calcium alginate (CA) shell that encapsulated Rg3@siTNF-α to form microbeads (CA@Rg3@siTNF-α), protecting the LNPs from premature degradation in the upper gastrointestinal tract. Upon colon-specific dissolution, CA@Rg3@siTNF-α released Rg3@siTNF-α, facilitating efficient macrophage uptake, rapid endosomal escape, and lipase-responsive siRNA release. Consequently, the microbeads alleviated UC by suppressing inflammation and oxidative stress, restoring epithelial barrier integrity, and rebalancing the gut microbiota. Collectively, this work presents a spatiotemporally controlled strategy for oral siRNA delivery with multi-mechanistic therapeutic actions.