Ionizable lipid nanoparticles deliver mRNA to pancreatic ? cells via macrophage-mediated gene transfer

Systemic messenger RNA (mRNA) delivery to organs outside the liver, spleen, and lungs remains challenging. To overcome this issue, we hypothesized that altering nanoparticle chemistry and administration routes may enable mRNA-induced protein expression outside of the reticuloendothelial system. Here, we describe a strat-egy for delivering mRNA potently and specifically to the pancreas using lipid nanoparticles. Our results show that delivering lipid nanoparticles containing cationic helper lipids by intraperitoneal administration produces robust and specific protein expression in the pancreas. Most resultant protein expression occurred within insulin-producing beta cells. Last, we found that pancreatic mRNA delivery was dependent on horizontal gene transfer by peritoneal macrophage exosome secretion, an underappreciated mechanism that influences the de-livery of mRNA lipid nanoparticles. We anticipate that this strategy will enable gene therapies for intractable pancreatic diseases such as diabetes and cancer.

Automated summary

Systemic delivery of mRNA to organs outside the liver, spleen, and lungs is difficult. This study presents a novel strategy using lipid nanoparticles to deliver mRNA specifically to the pancreas. Intraperitoneal administration of lipid nanoparticles containing cationic helper lipids results in robust and specific protein expression in the pancreas, with a majority occurring in insulin-producing beta cells. The delivery of pancreatic mRNA is found to be dependent on horizontal gene transfer by peritoneal macrophage exosome secretion. This strategy holds potential for gene therapies targeting pancreatic diseases such as diabetes and cancer.