Abstract
Lipid nanoparticles (LNPs) hold transformative potential for nucleic acid delivery, with applications ranging from clinical use, particularly in COVID-19 vaccines, to gene therapy and cancer immunotherapy. However, a major limitation lies in their preferential accumulation in the liver following intravenous administration, making most targets hard-to-reach. In this study, a novel platform called endogenous targeting lipid nanoparticles (ENDO), containing cholecalciferol (vitamin D3) as a fifth component is reported, that selectively delivers mRNA to the pancreas - a target previously inaccessible through intravenous administration. The top formulation, C-CholF3, demonstrates an unprecedented 99% pancreas selectivity with robust and sustained protein expression for up to 3 days in a dose-dependent manner with minimal toxicity that makes it suitable for repeat administration. This organ-specific delivery is proposed to be mediated by an endogenous targeting mechanism involving the Vitamin D receptor (VDR). C-CholF3 also enables selective pancreatic delivery of plasmid DNA and circular mRNA, underscoring its versatility and therapeutic potential. Furthermore, C-CholF3 exhibits pancreas-specific gene editing in the Ai14 transgenic mouse model, showing high expression of tdTomato in the β cells. These findings highlight its potential for translational applications in protein replacement and CRISPR/Cas9-mediated gene editing for currently incurable pancreatic diseases, including pancreatic cancer and diabetes.