Screening of sinapic acid as a polyphenol stabilizing agent for enhanced miR-124 delivery in ulcerative colitis therapy.

Ulcerative Colitis (UC) is a chronic intestinal disease with limited treatment options, where current therapies often suffer from inadequate efficacy and substantial side effects. While polyphenol-based nanocarriers show promise for nucleic acid delivery, a systematic screening approach to identify optimal polyphenols for this purpose remains unexplored. Therefore, we conducted a systematic screening of 110 natural polyphenols to develop an efficient miRNA delivery system for UC intervention. Sinapic acid (SA) was identified as the lead candidate and complexed with miR-124 mimics, followed by sequential encapsulation with a poly(amidoamine) (PAMAM) dendrimer and hyaluronic acid (HA) coating to form HPPR NPs. As expected, HPPR mediated efficient intracellular delivery of miR-124, leading to significant downregulation of the expression of IL-6R, CCL-2, STAT3, and their downstream genes in a murine model of dextran sulfate sodium (DSS)-induced acute colitis. HPPR also markedly suppressed the production of pro-inflammatory cytokines and facilitated intestinal mucosal regeneration. Moreover, the system effectively modulated gut microbiota homeostasis by enriching beneficial bacteria (Akkermansia and norank_f__Muribaculaceae) while simultaneously suppressing pathogenic bacteria (Escherichia-Shigella and Helicobacter). Collectively, this study not only establishes a polyphenol-based strategy for optimizing nucleic acid delivery but also presents a promising nanotherapeutic platform for UC treatment.