Ionizable lipid serves as the key functional component in lipid nanoparticles (LNPs) for efficient mRNA delivery. This study aims to systematically evaluate clinically approved ionizable lipid DLin-MC3-DMA and SM102-based LNPs for ocular mRNA delivery, with a comprehensive assessment of their physicochemical characteristics, delivery efficiency, and biodistribution patterns within the ocular microenvironment. Enhanced green fluorescence protein or Luc encoding mRNA-loaded LNPs were formulated using microfluidic mixing technology and characterized by dynamic light scattering, ζ-potential measurements, and cryogenic transmission electron microscopy imaging. The two LNP systems with different ionizable cationic lipids demonstrated distinct capabilities for in vitro mRNA transfection and intraocular mRNA delivery following intravitreal administration. Notably, the SM102-LNPs exhibited superior performance compared to the MC3-LNPs, characterized by significantly higher transfection efficiency in retinal cells in vitro, and more efficient ocular expression with minimal systemic distribution in vivo. Safety assessment demonstrated that intravitreal administration of SM102-LNPs maintained excellent long-term biocompatibility throughout a five-month study period. The superior performance of SM102-LNPs establishes a promising platform for ocular mRNA therapeutics.
DLin-MC3-DMA, the first FDA-approved ionizable lipid and a key component of lipid nanoparticles (LNPs), has enabled the clinical translation of RNA therapeutics. However, large-scale synthesis of DLin-MC3-DMA is limited by the challenging preparation of a symmetric secondary alcohol bearing two C18:2 alkyl chains, which typically requires multi-step procedures, stringent inert conditions and hazardous reagents, and affords only moderate yields. Here we report a tandem, mild synthesis strategy that converts methyl linoleate into a symmetric secondary alcohol bearing two C17:2 chains in 89% yield within 12 h. Subsequent esterification affords CLin-17, a structural analogue of DLin-MC3-DMA. LNPs formulated with CLin-17 exhibit high RNA encapsulation efficiency, a favorable pKa, and transfection efficiencies comparable to those of DLin-MC3-DMA-based LNPs across multiple cell lines, while maintaining low cytotoxicity and excellent storage stability. This work provides a facile approach to produce symmetric secondary alcohols for ionizable lipid synthesis, facilitating broader and more sustainable access to high-performance RNA delivery materials.
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