Reformulating lipid nanoparticles for organ-targeted mRNA accumulation and translation

Kexin Su, Lu Shi, Tao Sheng, Xinxin Yan, Lixin Lin, Chaoyang Meng, Shiqi Wu, Yuxuan Chen, Yao Zhang, Chaorong Wang, Zichuan Wang, Junjie Qiu, Jiahui Zhao, Tengfei Xu, Yuan Ping (), Zhen Gu () and Shuai Liu ()
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Kexin Su: Zhejiang University
Lu Shi: Zhejiang University
Tao Sheng: Zhejiang University
Xinxin Yan: Zhejiang University
Lixin Lin: Zhejiang University
Chaoyang Meng: Zhejiang University
Shiqi Wu: Zhejiang University
Yuxuan Chen: Zhejiang University
Yao Zhang: Zhejiang University
Chaorong Wang: Zhejiang University
Zichuan Wang: Zhejiang University
Junjie Qiu: Zhejiang University
Jiahui Zhao: Zhejiang University
Tengfei Xu: Zhejiang University
Yuan Ping: Zhejiang University
Zhen Gu: Zhejiang University
Shuai Liu: Zhejiang University

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract Fully targeted mRNA therapeutics necessitate simultaneous organ-specific accumulation and effective translation. Despite some progress, delivery systems are still unable to fully achieve this. Here, we reformulate lipid nanoparticles (LNPs) through adjustments in lipid material structures and compositions to systematically achieve the pulmonary and hepatic (respectively) targeted mRNA distribution and expression. A combinatorial library of degradable-core based ionizable cationic lipids is designed, following by optimisation of LNP compositions. Contrary to current LNP paradigms, our findings demonstrate that cholesterol and phospholipid are dispensable for LNP functionality. Specifically, cholesterol-removal addresses the persistent challenge of preventing nanoparticle accumulation in hepatic tissues. By modulating and simplifying intrinsic LNP components, concurrent mRNA accumulation and translation is achieved in the lung and liver, respectively. This targeting strategy is applicable to existing LNP systems with potential to expand the progress of precise mRNA therapy for diverse diseases.

Date: 2024
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DOI: 10.1038/s41467-024-50093-7

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