Peptide codes for organ-selective mRNA delivery PMID: 40890497

ADC Targets in Oncology

2026-04-10

Peptide codes for organ-selective mRNA delivery

Nat Mater. 2025 Sep 1. doi: 10.1038/s41563-025-02331-6.

Tie Chang ¹ , Yifan Zheng ¹ , Mingrui Jiang ² , Siqi Jia ³ , Jianbo Bai ¹ , Zhi Zheng ¹ , Shixin Li ⁴ ⁵ ⁶ , Jia Guo ¹ , Yue Wang ⁷ ⁸ , Yiting Wang ⁷ , Haixia Liu ⁷ , Jianlin Liu ⁷ , Liangyu Ni ³ , Xingdi Cheng ⁹ , Shuai Liu ⁹ , Huijuan Zhang ¹⁰ , Wei Pi ¹ , Feng Lin ¹ ¹¹ , Shiyi Liu ¹ , Weijian Wang ¹² , Guannan Wang ¹² , Leyun Wang ¹³ ¹⁴ , Lei Miao ¹⁰ ¹⁵ , Xueguang Lu ⁹ , Ziqing Deng ⁷ ⁸ , Bing Bai ⁴ ⁵ ⁶ , Zhao Qin ² , Huajian Gao ¹⁶ , Yue Shao ¹⁷

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. [email protected].
17. Institute of Biomechanics and Medical Engineering, Applied Mechanics Laboratory, Department of Engineering Mechanics, Tsinghua University, Beijing, China. [email protected].

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.