Development of gene delivery systems for liver diseases treatment and cancer treatment

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First, lipid nanoparticles (LNPs) based on a library of molecularly-diverse ionizable lipids were screened in vitro for selective mRNA delivery to aHSCs cell line, LX-2. Second, the top-performing candidates were screened and optimized in vivo in mice undergoing liver fibrosis. The composition and physico-chemical properties of LNPs were tweaked to manipulate the endogenous protein corona that is formed around LNPs and subsequently enable ligand-free targeting. Third, the biosafety of the optimized LNPs was intensively evaluated upon either acute dose escalation or chronic administration. Fourth, the underlying mechanism for selective delivery of LNPs to aHSCs in vivo was explored using a systematic strategy. Fifth, the selected candidates were also investigated for siRNA delivery to aHSCs in vivo. Eventually, a therapeutic strategy was established based on the siRNA-mediated reprogramming of aHSCs into the quiescent state (qHSCs).This project enabled identification of the optimum conditions for ligand-free targeting of aHSCs in vivo for the first time. Moreover, a successful gene therapy-based strategy for the treatment of liver fibrosis was established and evaluated with a promising clinical potential.