Citation: Min Zhao, Huan-Ni Liu, Hai-Xin Xie, Hao-Yuan Yu, Jing-Song Yang, Na-Hui Liu, Jia-Qi Chen, Lu-Xin Qie, Zi-Juan Yi, Tian-Jiao Zhou, Lei Xing, Xian Wu Cheng, Yi Wang, Hu-Lin Jiang. Mitochondria-targeted lipid nanoparticles to rescue mitochondrial complex Ⅰ deficiency for Leber's hereditary optic neuropathy therapy[J]. Chinese Chemical Letters, ;2026, 37(12): 112360. doi: 10.1016/j.cclet.2026.112360 shu

Mitochondria-targeted lipid nanoparticles to rescue mitochondrial complex Ⅰ deficiency for Leber's hereditary optic neuropathy therapy

Min Zhao ^a ,
Huan-Ni Liu ^a ,
Hai-Xin Xie ^a ,
Hao-Yuan Yu ^a ,
Jing-Song Yang ^a ,
Na-Hui Liu ^a ,
Jia-Qi Chen ^a ,
Lu-Xin Qie ^a ,
Zi-Juan Yi ^a ,
Tian-Jiao Zhou ^a ,
Lei Xing ^a ,
Xian Wu Cheng ^{b, *,} ,
Yi Wang ^{a, *,} ,
Hu-Lin Jiang ^{a, b, c, d, *,}

a.
State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
b.
Jilin Provincial Key Laboratory of Stress and Cardiovascular Disease, Department of Cardiology and Hypertension, Yanbian University Hospital, Yanji 133002, China
c.
Joint International Research Laboratory of Target Discovery and New Drug Innovation, MOE, China Pharmaceutical University, Nanjing 210009, China
d.
Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, South Korea

chengxw@ybu.edu.cn

wangyi950825@163.com

jianghulin3@163.com

Received Date: 16 October 2025
Revised Date: 29 December 2025
Accepted Date: 3 January 2026
Available Online: 5 January 2026

Figures(5)

Mitochondrial gene delivery for functional compensation of defective proteins represents a promising therapeutic strategy for currently untreatable mitochondrial disorders. However, the double-membrane structure of mitochondrial poses a fundamental barrier for the transport of genetic therapeutics into the organelle. Here, we report a novel mitochondria-targeted fluorinated lipid nanoparticle (F₆ mtLNP) for efficient mitochondrial gene delivery. F₆ mtLNP successfully overcame mitochondrial barriers and delivered the therapeutic NDI1 gene into the mitochondrial matrix leveraging the mitochondrial targeting capacity of the mitochondrial targeting signal (MTS) peptide combined with the superior membrane affinity and penetration capability of F₆ lipid. In a rotenone-induced Leber's hereditary optic neuropathy (LHON) model characterized by complex Ⅰ deficiency, F₆ mtLNP mediated superior functional protein expression, leading to significant restoration of complex Ⅰ activity and consequent amelioration of disease symptoms. Collectively, our findings established F₆ mtLNP as a promising platform to overcome the mitochondrial membrane barrier for effective functional gene delivery, offering a potential therapeutic strategy for LHON and other mitochondrial complex Ⅰ deficiency-related mitochondrial disorders.
- Mitochondria-targeted delivery,
- Lipid nanoparticle,
- Ionizable lipid,
- Mitochondrial complex Ⅰ deficiency,
- Mitochondrial disorders
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