Pancreatic-targeted lipid nanoparticles based on organ capsule filtration PMID: 41741655

ADC Targets in Oncology

2026-04-10

Pancreatic-targeted lipid nanoparticles based on organ capsule filtration

Nature. 2026 Apr;652(8108):220-229. doi: 10.1038/s41586-026-10158-7.

Jiaqi Lei ^# ¹ , Kai Yang ^# ¹ , Wanyue Cao ^# ² ³ ⁴ , Shaolong Qi ¹ , Xianlong Du ¹ , Hongjian Li ⁵ , Yangfan Wang ¹ , Jinqun Gan ¹ , Yunxuan Feng ¹ , Yongcan Li ¹ , Wenjie Zhang ¹ , Bing Bai ¹ , Xin Lin ⁵ , Xinhui Su ⁶ , Qi Zhang ⁷ ⁸ ⁹ , Tingbo Liang ¹⁰ ¹¹ ¹² , Guocan Yu ¹³ ¹⁴

Affiliations

1. Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Department of Chemistry, Tsinghua University, Beijing, P. R. China.
2. Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China.
3. MOE Joint International Research Laboratory of Pancreatic Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China.
4. Cancer Center, Zhejiang University, Hangzhou, P. R. China.
5. Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, P. R. China.
6. Department of Nuclear Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China.
7. Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China. [email protected].
8. MOE Joint International Research Laboratory of Pancreatic Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China. [email protected].
9. Cancer Center, Zhejiang University, Hangzhou, P. R. China. [email protected].
10. Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China. [email protected].
11. MOE Joint International Research Laboratory of Pancreatic Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China. [email protected].
12. Cancer Center, Zhejiang University, Hangzhou, P. R. China. [email protected].
13. Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Department of Chemistry, Tsinghua University, Beijing, P. R. China. [email protected].
14. Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, P. R. China. [email protected].
# Contributed equally.

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.