Science子刊：清华大学喻国灿团队开发新型mRNA-LNP疗法，治疗脂肪肝及相关肝癌

Core Viewpoint - The study highlights the development of a vitamin E-functionalized lipid nanoparticle (Def-LNP) for delivering mRNA encoding T-cell protein tyrosine phosphatase (TCPTP), aiming to remodel the immune microenvironment and improve immunotherapy for Metabolism-Associated Fatty Liver Disease (MAFLD) and related hepatocellular carcinoma (HCC) [1][2]. Group 1: MAFLD and HCC Overview - MAFLD is a significant global health burden, encompassing conditions from simple steatosis to HCC, and presents challenges in treatment due to the complex liver microenvironment [4]. - mRNA-based therapies offer a potential shift in treatment paradigms for MAFLD and HCC by enabling in situ protein expression, but achieving sustained high concentrations of functional proteins is crucial for efficacy [4]. Group 2: TCPTP as a Therapeutic Target - TCPTP is identified as a promising therapeutic target for MAFLD due to its role in the STAT signaling pathway, but its therapeutic potential is limited by its susceptibility to oxidation in the liver's oxidative microenvironment [4][5]. Group 3: Development of Def-LNP - The research team incorporated vitamin E into the lipid nanoparticle design to combat TCPTP oxidation and enhance the effectiveness of mRNA-based therapies [5]. - Def-LNP was constructed using a phosphatidylcholine derived from vitamin E, optimized through orthogonal screening to identify the best components for the formulation [5]. Group 4: Efficacy of Def-LNP - In preclinical models, Def-LNP demonstrated superior delivery efficiency, stability, and biocompatibility compared to commercially available FDA-approved LNP formulations [7]. - Administration of Def-LNP delivering TCPTP mRNA effectively reprogrammed liver metabolism and immune responses, eliminating steatohepatitis and preventing HCC development [7][9]. Group 5: Implications for Future Treatments - Def-LNP@mRNA TCPTP represents a potential new strategy for treating MAFLD and HCC, offering a novel approach to immunotherapy for metabolic liver diseases [9].