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Pancreatic-targeted lipid nanoparticles based on organ capsule filtration

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TL;DR

Researchers developed a pancreatic-targeted lipid nanoparticle (AH-LNP) that selectively accumulates in the pancreas via capsule filtration and receptor-mediated endocytosis. This enables efficient mRNA delivery for genome editing and cancer therapy, showing promise in animal models and clinical translation.

Key Takeaways

  • •AH-LNP uses size enlargement and capsule filtration for precise pancreatic targeting, enhancing mRNA delivery.
  • •It enables effective genome editing in the pancreas for treating autoimmune diseases and improves antitumour efficacy in cancer models.
  • •Safety and efficacy were validated in multiple animal models, including non-human primates, supporting potential clinical applications.

Tags

Biomedical engineeringDNA and RNAScienceHumanities and Social Sciencesmultidisciplinary

Abstract

Achieving pancreatic-targeted delivery marks a breakthrough in treating pancreatic diseases, yet precise delivery remains challenging1. Here we identify an explicit and universal principle for pancreatic-selective delivery and propose a pancreatic-targeted lipid nanoparticle (AH-LNP) for mRNA delivery. AH-LNP exhibits size enlargement after assembly with proteins, facilitating capsule-filter-mediated pancreas-selective accumulation and receptor-mediated endocytosis, thereby boosting the pancreatic-targeted ability. Benefiting from this, AH-LNP enables precise and efficient genome editing in the pancreas through the delivery of Cas9 mRNA and single guide RNA (sgRNA), exhibiting promising potential in the treatment of autoimmune pancreatic diseases. Furthermore, pancreatic-targeted delivery of mRNA encoding therapeutic cytokines through AH-LNP demonstrates superior antitumour efficacy when combined with a cancer vaccine or chimeric antigen receptor T cell therapy in multiple pancreatic cancer models. The safety and pancreatic mRNA delivery of AH-LNP were verified in multiple animal models, including non-human primates, demonstrating great promise for clinical translation. Our findings highlight the transformative potential of this pancreatic-targeted mechanism and the derived LNP platform, opening avenues for developing precision therapeutics against diverse pancreatic diseases.

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Fig. 1: The role of capsules in organ-targeted delivery.
Fig. 2: Establishment of an AA-lipid library and formulation optimization of AA-LNPs.
Fig. 3: Cross-species verification of pancreatic-targeted performance of AH-LNP.
Fig. 4: VLDLR-mediated pancreatic uptake.
Fig. 5: Antitumour therapy using AH-LNP as the vehicle.

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Data availability

All data generated and supporting the findings of this study are available within the Article and its Supplementary Information. The raw sequencing data reported in this study have been deposited at the Genome Sequence Archive under accession number PRJCA051840. Data for VLDLR expression across various organs in humans are accessible in the DISCO36. Data on PD-L1 expression in pancreatic tumours and its correlation with survival are available in the GEPIA37. Source data are provided with this paper.

References

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