A clinically relevant retrograde intraductal injection (RIDI) for lipid nanoparticles-mediated base editing in the pancreas.

Gene therapy offers potential curative strategies for many pancreatic diseases, including diabetes and inherited pancreatitis. However, their clinical translation has been hindered by the lack of an effective delivery platform. Lipid nanoparticles (LNPs) are established as a leading non-viral delivery system for nucleic acids; however, their tropism is limited to the liver following systemic administration. In this study, we evaluated retrograde intraductal injection (RIDI), a clinically relevant and routinely performed endoscopic technique, as a direct delivery route for LNPs into pancreatic tissue. RIDI of Cre mRNA-loaded LNPs resulted in the transfection of approximately 47% of acinar cells, leading to robust recombination. Extending this approach to gene editing, we observed ~20-30% of gene editing and 5% base editing in mouse models. Collectively, these findings establish RIDI as a viable strategy for pancreas-targeted LNP administration, highlighting its potential to enable gene therapy and gene editing in pancreatic diseases.