Muscle-specific gene editing therapy via mammalian fusogen-directed virus-like particles

Shi-Kun Zhou, Jing-Tong Luo, Yi-Fang Chen, Zi-Dong Lu, Qiu-Hong Jian, Shui-Qing Jiang, Jing Li, Xue-Qin Zhang, Xin-Yu Tan, Xian-Zhu Yang, Cong-Fei Xu () and Jun Wang ()
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Shi-Kun Zhou: Guangzhou International Campus
Jing-Tong Luo: Guangzhou International Campus
Yi-Fang Chen: Guangzhou International Campus
Zi-Dong Lu: South China University of Technology
Qiu-Hong Jian: Guangzhou International Campus
Shui-Qing Jiang: Guangzhou International Campus
Jing Li: Guangzhou International Campus
Xue-Qin Zhang: Guangzhou International Campus
Xin-Yu Tan: Guangzhou International Campus
Xian-Zhu Yang: Guangzhou International Campus
Cong-Fei Xu: Guangzhou International Campus
Jun Wang: Guangzhou International Campus

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract Muscle genetic defects can lead to impaired movement, respiratory failure, and other severe symptoms. The development of curative therapies is challenging due to the need for the delivery of gene-editing tools into skeletal muscle cells throughout the body. Here, we use muscular fusogens (Myomaker and Myomerger) to engineer muscle-specific virus-like particles (MuVLPs) for the systemic delivery of gene-editing tools. We demonstrate that MuVLPs can be loaded with diverse payloads, including EGFP, Cre and Cas9/sgRNA ribonucleoproteins (Cas9 RNPs), and can be delivered into skeletal muscle cells via targeted membrane fusion. Systemic administration of MuVLPs carrying Cas9 RNPs enables skeletal muscle-specific gene editing, which excised the exon containing a premature terminator codon mutation in a mouse model for Duchenne muscular dystrophy (DMD). This treatment restores dystrophin expression in various skeletal muscle tissues, including the diaphragm, quadriceps, tibialis anterior, gastrocnemius, and triceps. As a result, the treated mice exhibit a significantly increased capacity for exercise and endurance. This study established a platform for precise gene editing in skeletal muscle tissues.

Date: 2025
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DOI: 10.1038/s41467-025-64200-9

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