Peptide codes for organ-selective mRNA delivery

Tie Chang¹, Yifan Zheng¹, Mingrui Jiang², Siqi Jia³, Jianbo Bai¹, Zhi Zheng¹, Shixin Li^{4

5

6}, Jia Guo¹, Yue Wang^{7

8}, Yiting Wang⁷, Haixia Liu⁷, Jianlin Liu⁷, Liangyu Ni³, Xingdi Cheng⁹, Shuai Liu⁹, Huijuan Zhang¹⁰, Wei Pi¹, Feng Lin^{1

11}, Shiyi Liu¹, Weijian Wang¹², Guannan Wang¹², Leyun Wang^{13

14}, Lei Miao^{10

15}, Xueguang Lu⁹, Ziqing Deng^{7

8}, Bing Bai^{4

5

6}, Zhao Qin², Huajian Gao¹⁶, Yue Shao¹⁷

Affiliations

¹ Institute of Biomechanics and Medical Engineering, Applied Mechanics Laboratory, Department of Engineering Mechanics, Tsinghua University, Beijing, China.
² Department of Civil and Environmental Engineering, Syracuse University, Syracuse, NY, USA.
³ Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Key Laboratory for Neuroscience, Ministry of Education/National Health Commission and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China.
⁴ State Key Laboratory of Primate Biomedical Research, Kunming University of Science and Technology, Kunming, China.
⁵ Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, China.
⁶ Yunnan Key Laboratory of Primate Biomedical Research, Kunming, China.
⁷ BGI Research, Beijing, China.
⁸ Shanxi Medical University-BGI Collaborative Center for Future Medicine, Shanxi Medical University, Taiyuan, China.
⁹ Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Colloid, Interface and Chemical Thermodynamics, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China.
¹⁰ State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China.
¹¹ Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, China.
¹² College of Civil Engineering and Architecture, Zhejiang University, Hangzhou, China.
¹³ Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China.
¹⁴ Xiamen Key Laboratory of Cardiovascular Diseases, Xiamen, China.
¹⁵ Beijing Key Laboratory of Molecular Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, China.
¹⁶ Mechano-X Institute, Applied Mechanics Laboratory, Department of Engineering Mechanics, Tsinghua University, Beijing, China. gao.huajian@tsinghua.edu.cn.
¹⁷ Institute of Biomechanics and Medical Engineering, Applied Mechanics Laboratory, Department of Engineering Mechanics, Tsinghua University, Beijing, China. yshao@tsinghua.edu.cn.

PMID: 40890497
DOI: 10.1038/s41563-025-02331-6

Peptide codes for organ-selective mRNA delivery

Tie Chang et al. Nat Mater. 2025.

. 2025 Sep 1.

doi: 10.1038/s41563-025-02331-6. Online ahead of print.

Authors

Affiliations

¹ Institute of Biomechanics and Medical Engineering, Applied Mechanics Laboratory, Department of Engineering Mechanics, Tsinghua University, Beijing, China.
² Department of Civil and Environmental Engineering, Syracuse University, Syracuse, NY, USA.
³ Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Key Laboratory for Neuroscience, Ministry of Education/National Health Commission and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China.
⁴ State Key Laboratory of Primate Biomedical Research, Kunming University of Science and Technology, Kunming, China.
⁵ Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, China.
⁶ Yunnan Key Laboratory of Primate Biomedical Research, Kunming, China.
⁷ BGI Research, Beijing, China.
⁸ Shanxi Medical University-BGI Collaborative Center for Future Medicine, Shanxi Medical University, Taiyuan, China.
⁹ Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Colloid, Interface and Chemical Thermodynamics, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China.
¹⁰ State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China.
¹¹ Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, China.
¹² College of Civil Engineering and Architecture, Zhejiang University, Hangzhou, China.
¹³ Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China.
¹⁴ Xiamen Key Laboratory of Cardiovascular Diseases, Xiamen, China.
¹⁵ Beijing Key Laboratory of Molecular Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, China.
¹⁶ Mechano-X Institute, Applied Mechanics Laboratory, Department of Engineering Mechanics, Tsinghua University, Beijing, China. gao.huajian@tsinghua.edu.cn.
¹⁷ Institute of Biomechanics and Medical Engineering, Applied Mechanics Laboratory, Department of Engineering Mechanics, Tsinghua University, Beijing, China. yshao@tsinghua.edu.cn.

PMID: 40890497
DOI: 10.1038/s41563-025-02331-6

Abstract

Organ-selective delivery of messenger RNA (mRNA) is critical for fulfilling the therapeutic potential of mRNA-based gene and protein replacement technologies. Despite clinical advances in the hepatic delivery of mRNA using lipid nanoparticles (LNPs), current strategies for extrahepatic-organ-selective mRNA delivery still have limitations. Here we report a peptide-encoded organ-selective targeting (POST) method for the delivery of mRNA to extrahepatic organs after systemic administration, which is based on the modular tuning of LNPs through surface engineering with specific amino acid sequences (POST codes). Molecular dynamics simulations and in vitro and in vivo testing show that the organ-selective targeting of POST results from the specific protein corona of the peptide-decorated LNPs, which is established from the mechanical optimization of the binding affinities between peptides with a particular sequence and plasma proteins. This approach can be used for the organ-selective delivery of different ribonucleic acids and multiple gene editing machinery. Overall, the POST platform creates a modular repertoire for LNP surface engineering for directing organ tropism, broadening the scope and versatility of organ-selective delivery.

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Conflict of interest statement

Competing interests: Y.S. and T.C. have filed a patent in the China National Intellectual Property Administration (patent no. 202310977908.7) based on the POST platform developed in this study. The remaining authors declare no competing interests.

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Peptide codes for organ-selective mRNA delivery

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Peptide codes for organ-selective mRNA delivery

Authors

Affiliations

Abstract

Conflict of interest statement

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