Adipocyte-selective mRNA lipid nanoparticles for cell programming with machine learning analysis

Adipose tissue plays a crucial role in energy metabolism and endocrine signaling. White adipose tissue (WAT), in particular, is a compelling target for therapeutic interventions in metabolic diseases due to its secretory capacity and abundance. Gene therapies hold promise for reprogramming adipocytes to enhance energy metabolism and facilitate the secretion of therapeutic proteins. Lipid nanoparticles (LNPs) are a promising non-viral delivery vehicle for nucleic acids, but achieving adipocyte-specific transfection is challenging due to the cellular diversity of adipose tissue. Here, we employed a multi-step screening method to optimize mRNA LNPs for adipocyte-preferential transfection, followed by machine learning analysis to identify the features that drive adipocyte selectivity. Furthermore, we demonstrated potent and selective LNP-mediated mRNA delivery to adipocytes in vivo. Our findings highlight the importance of optimizing LNP composition to enhance mRNA transfection efficiency in adipocytes, providing a promising strategy for adipocyte engineering and therapeutic applications.