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RNA nanotherapeutics with fibrosis overexpression and retention for MASH treatment

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机构： [1]State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China. [2]Beijing Key Laboratory of Molecular Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, China. [3]Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, China. [4]Institute of Cardiovascular Sciences and State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing, China. [5]Chinese Institute for Brain Research, Beijing, China. [6]China Spallation Neutron Source, Institute of High Energy Physics, Chinese Academy of Science, Dongguan, China. [7]Department of Surgery, Nantong Tumor Hospital, Tumor Hospital Affiliated to Nantong University, Nantong, China. [8]Keymed Biosciences (Chengdu) Limited, Chengdu, Sichuan, China. [9]Key Laboratory of Colloid, Interface and Chemical Thermodynamics, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China. [10]MOE Key Laboratory of Bio-Intelligent Manufacturing, School of Bioengineering, Dalian University of Technology, Dalian, China. [11]Interdisplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China. [12]Department of Bioengineering, UC Berkeley, Berkeley, CA, USA. [13]Peking University-Yunnan Baiyao International Medical Research Center, Beijing, China.

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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.© 2024. The Author(s).

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第一作者：

第一作者机构： [1]State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China. [2]Beijing Key Laboratory of Molecular Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, China.

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通讯机构： [1]State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China. [2]Beijing Key Laboratory of Molecular Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, China. [13]Peking University-Yunnan Baiyao International Medical Research Center, Beijing, China.

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