Ionizable lipid is a key component of lipid nanoparticle (LNP) for mRNA delivery. However, the discovery of new lipid scaffolds remains constrained by the limited availability of efficient synthetic platforms capable of generating structurally diverse libraries. Here, we report a photochemistry-based ionizable lipid library (PILL) platform that enables the rapid discovery of ionizable lipids for mRNA delivery. Using a visible-light-driven multicomponent reaction under 427 nm irradiation, 275 α-branched amine-containing ionizable lipids were generated in a one-pot process from amines, aldehydes, and boronic acids under mild conditions. This modular photochemical strategy enabled the rapid construction of a structurally diverse lipid library that was directly integrated with purification-free in vitro screening and subsequent in vivo validation. A18B8C14 was identified as a lead ionizable lipid candidate for mRNA delivery, and the optimized A18B8C14-LNP formulation exhibited substantially higher in vivo gene expression than the benchmark MC3-based LNP while maintaining a favorable safety profile. In addition, organ-specific delivery could be achieved by adjusting the A18B8C14-LNP formulation according to the selective organ targeting (SORT) strategy. Together, these results establish photochemistry as a practical platform for ionizable lipid discovery and provide a versatile framework for the development of next-generation LNP systems for nucleic acid therapeutics.
Simin Chun, Hyorim Nam, Donghyun Lee et al.· Journal of the American Chem...· 0 citations
In a recent publication in Cell Stem Cell , Cai et al. 1 employed an in vivo Perturb-seq strategy to systematically identify molecular barriers that limit direct cardiac reprogramming following myocardial infarction (MI). This study provides a conceptual and technological framework for improving fi broblast-to-cardiomyocyte conversion in vivo and identi fi es a key regulatory pathway that can be targeted to enhance cardiac regeneration. The limited regenerative capacity of the adult mammalian heart and the resulting loss of functional myocardium after MI under-score the urgent need for strategies that can restore cardiac muscle and improve heart function. Direct cardiac reprogramming has emerged as a promising approach for myocardial repair whereby fi broblasts can be directly converted into induced cardiomyocytes (iCMs). Pioneering studies have demonstrated that de fi ned transcription factors including Mef2c, Gata4, and Tbx5 (collectively referred to as MGT), and later extended combinations such as Myocd and Sall4 (collectively termed MGTMyoS) can induce transdifferentiation of fi broblasts to a cardiomyocyte-like state both in vitro and in vivo. 2 – 4 However, the ef fi ciency and fi delity of in vivo direct reprogramming remain low, representing a major obstacle for clinical translation. This limitation is thought to arise, at least in part, from the complex post-injury microenvironment, where in fl ammatory signaling, extracellular matrix remodeling, and cellular stress responses collectively constrain cell fate conversion. Despite growing recognition of these in fl uences, the molecular mechanisms that restrict cardiac reprogramming ef fi ciency in the injured heart have not been de fi ned. A comprehensive and quantitative understanding of the molecular barriers operating in this context is therefore
Johnny Kim, Hans R. Schöler, Kee-Pyo Kim· Signal Transduction and Targ...· 0 citations
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