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Achieving targeted delivery to the pancreas marks a breakthrough in treating pancreatic diseases, but precise delivery still remains a challenge. In this paper, we identified clear and general principles for pancreas-selective delivery and proposed a type of pancreas-targeted lipid nanoparticle (AH-LNP) for mRNA delivery. AH-LNPs show an increase in size after protein assembly, which promotes pancreas-selective accumulation via endocytic pathways and receptor-mediated uptake, enhancing pancreatic targeting. Based on this, AH-LNPs enable precise and efficient genome editing in the pancreas by delivering Cas9 mRNA and single guide RNA (sgRNA), showing promising potential for treating autoimmune pancreatic diseases. In addition, targeting delivery of mRNA encoding therapeutic cytokines via AH-LNPs in various pancreatic cancer models showed superior anti-tumor effects when combined with cancer vaccines or chimeric antigen receptor T cell therapy. The safety of AH-LNPs and their pancreas mRNA delivery has been validated in multiple animal models, including non-human primates, demonstrating great potential for clinical translation. Our findings highlight the transformative potential of this pancreas-targeting mechanism and its derived LNP platform, opening up new avenues for precision treatment for various pancreatic diseases.
Reference:
DOI: 10.1038/s41586-026-10158-7
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