Chang Tie, Zheng Yifan, Jiang Mingrui, Jia Siqi, Bai Jianbo, Zheng Zhi, Li Shixin, Guo Jia, Wang Yue, Wang Yiting, Liu Haixia, Liu Jianlin, Ni Liangyu, Cheng Xingdi, Liu Shuai, Zhang Huijuan, Pi Wei, Lin Feng, Liu Shiyi, Wang Weijian, Wang Guannan, Wang Leyun, Miao Lei, Lu Xueguang, Deng Ziqing, Bai Bing, Qin Zhao, Gao Huajian, Shao Yue
Institute of Biomechanics and Medical Engineering, Applied Mechanics Laboratory, Department of Engineering Mechanics, Tsinghua University, Beijing, China.
Department of Civil and Environmental Engineering, Syracuse University, Syracuse, NY, USA.
Nat Mater. 2025 Sep 1. doi: 10.1038/s41563-025-02331-6.
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.
信使核糖核酸(mRNA)的器官选择性递送对于实现基于mRNA的基因和蛋白质替代技术的治疗潜力至关重要。尽管使用脂质纳米颗粒(LNP)进行肝脏mRNA递送已取得临床进展,但目前用于肝外器官选择性mRNA递送的策略仍存在局限性。在此,我们报告了一种肽编码的器官选择性靶向(POST)方法,用于在全身给药后将mRNA递送至肝外器官,该方法基于通过用特定氨基酸序列(POST编码)进行表面工程对LNP进行模块化调控。分子动力学模拟以及体外和体内测试表明,POST的器官选择性靶向源于肽修饰的LNP的特定蛋白质冠层,其由具有特定序列的肽与血浆蛋白之间结合亲和力的机械优化建立而成。这种方法可用于不同核糖核酸和多种基因编辑机制的器官选择性递送。总体而言,POST平台为LNP表面工程创建了一个模块化库,用于指导器官趋向性,拓宽了器官选择性递送的范围和通用性。