RNA nanotherapeutics with fibrosis overexpression and retention for MASH treatment

Xinzhu Shan, Zhiqiang Zhao, Pingping Lai, Yuxiu Liu, Buyao Li, Yubin Ke, Hanqiu Jiang, Yilong Zhou, Wenzhe Li, Qian Wang, Pengxia Qin, Yizhe Xue, Zihan Zhang, Chenlong Wei, Bin Ma, Wei Liu, Cong Luo, Xueguang Lu, Jiaqi Lin, Li Shu, Yin Jie, Xunde Xian, Derfogail Delcassian, Yifan Ge and Lei Miao ()
Additional contact information
Xinzhu Shan: Peking University
Zhiqiang Zhao: Peking University
Pingping Lai: Peking University
Yuxiu Liu: Chinese Institute for Brain Research
Buyao Li: Peking University
Yubin Ke: Chinese Academy of Science
Hanqiu Jiang: Chinese Academy of Science
Yilong Zhou: Tumor Hospital Affiliated to Nantong University
Wenzhe Li: Peking University
Qian Wang: Peking University
Pengxia Qin: Peking University
Yizhe Xue: Peking University
Zihan Zhang: Peking University
Chenlong Wei: Peking University
Bin Ma: Peking University
Wei Liu: Keymed Biosciences (Chengdu) Limited
Cong Luo: Shenyang Pharmaceutical University
Xueguang Lu: Chinese Academy of Sciences
Jiaqi Lin: Dalian University of Technology
Li Shu: Chinese Academy of Sciences
Yin Jie: Chinese Institute for Brain Research
Xunde Xian: Peking University
Derfogail Delcassian: UC Berkeley
Yifan Ge: Chinese Academy of Sciences
Lei Miao: Peking University

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract Metabolic dysfunction-associated steatohepatitis (MASH) poses challenges for targeted delivery and retention of therapeutic proteins due to excess extracellular matrix (ECM). Here we present a new approach to treat MASH, termed “Fibrosis overexpression and retention (FORT)”. In this strategy, we design (1) retinoid-derivative lipid nanoparticle (LNP) to enable enhanced mRNA overexpression in fibrotic regions, and (2) mRNA modifications which facilitate anchoring of therapeutic proteins in ECM. LNPs containing carboxyl-retinoids, rather than alcohol- or ester-retinoids, effectively deliver mRNA with over 10-fold enhancement of protein expression in fibrotic livers. The carboxyl-retinoid rearrangement on the LNP surface improves protein binding and membrane fusion. Therapeutic proteins are then engineered with an endogenous collagen-binding domain. These fusion proteins exhibit increased retention in fibrotic lesions and reduced systemic toxicity. In vivo, fibrosis-targeting LNPs encoding fusion proteins demonstrate superior therapeutic efficacy in three clinically relevant male-animal MASH models. This approach holds promise in fibrotic diseases unsuited for protein injection.

Date: 2024
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DOI: 10.1038/s41467-024-51571-8

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