RNA nanotherapeutics with fibrosis overexpression and retention for MASH treatment PMID: 39191801

ADC Targets in Oncology

2026-04-10

RNA nanotherapeutics with fibrosis overexpression and retention for MASH treatment

Nat Commun. 2024 Aug 27;15(1):7263. doi: 10.1038/s41467-024-51571-8.

Xinzhu Shan ^# ¹ ² , Zhiqiang Zhao ^# ¹ ² ³ , Pingping Lai ⁴ , Yuxiu Liu ⁵ , Buyao Li ² , Yubin Ke ⁶ , Hanqiu Jiang ⁶ , Yilong Zhou ⁷ , Wenzhe Li ¹ , Qian Wang ¹ , Pengxia Qin ² , Yizhe Xue ² , Zihan Zhang ² , Chenlong Wei ² , Bin Ma ¹ ² , Wei Liu ⁸ , Cong Luo ³ , Xueguang Lu ⁹ , Jiaqi Lin ¹⁰ , Li Shu ¹¹ , Yin Jie ⁵ , Xunde Xian ⁴ , Derfogail Delcassian ¹² , Yifan Ge ¹¹ , Lei Miao ¹³ ¹⁴ ¹⁵

Affiliations

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. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China. [email protected].
14. Beijing Key Laboratory of Molecular Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, China. [email protected].
15. Peking University-Yunnan Baiyao International Medical Research Center, Beijing, China. [email protected].
# Contributed equally.

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.