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, Lei, Miao

Nature Communications |

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.