Virus-inspired lipopeptide-derived nucleic acid delivery to cartilage for osteoarthritis therapy

Yu Fu, Yulan Huang, Yunjiao Wang, Zhenlan Fu, Wenyun Cai, Lu Wang, Yuchun Wu, Xing Zhou, Zhongyi Ma, Zhigang Xu, Yaqin Tang, Jing Xie, Jiayun Jiang, Robert J. Lee () and Chong Li ()
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Yu Fu: Southwest University
Yulan Huang: Southwest University
Yunjiao Wang: Army Medical University (Third Military Medical University)
Zhenlan Fu: Army Medical University (Third Military Medical University)
Wenyun Cai: Southwest University
Lu Wang: Southwest University
Yuchun Wu: Southwest University
Xing Zhou: Chongqing University of Technology
Zhongyi Ma: Southwest University
Zhigang Xu: Southwest University
Yaqin Tang: Chongqing University of Technology
Jing Xie: Chongqing University of Technology
Jiayun Jiang: Army Medical University (Third Military Medical University)
Robert J. Lee: The Ohio State University
Chong Li: Southwest University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Cartilage-targeted gene therapy is promising for osteoarthritis (OA) treatment, though its potency critically depends on the effectiveness of delivery vectors. Here, we modularly develop a series of non-pathogenic, virus-inspired lipopeptide-based nanoparticles (VPN) tailored to deliver nucleic acids to cartilage. The cationic moiety of lipopeptide with variable arginine and histidine residues is the key functional component, and screened by in vitro performance. The optimized VPN-2 with a moiety of –[(R)5-(H)4]2- facilitates sufficient endocytosis and effective lysosomal escape, achieving about 2.5-fold improvement in transfection potency over conventional lipid nanoparticles. To address the tradeoff between penetration and retention within articular cartilage, si-VPN-2 is further formulated into ROS-responsive nano-in-gel system, which turns out to alleviate cartilage degeneration in surgical ACTL mice, and further synergizes with methylprednisolone to implement superior joint protection in PTOA mice. Our study underscores the platform’s potential of VPN as cartilage-targeted RNA delivery vector for innovative OA therapy.

Date: 2025
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DOI: 10.1038/s41467-025-64212-5

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