Targeted mRNA Delivery Using Bispecific Antibody-Lipid Nanoparticle Complexes.
Lipid nanoparticles (LNPs) are highly modular drug nanocarriers that have significantly progressed in the development and application of novel RNA therapeutics. While instrumental in current vaccine and hepatic gene therapy applications, extrahepatic LNP delivery remains a challenging hurdle, severely limiting clinical applications for individualized therapies that require cellular- and tissue-specific enrichment. Novel platform development remains needed to generate targeted LNPs capable of modeling targeted uptake in vitro prior to in vivo applications. Herein, we developed and utilized an antibody-based targeting bispecific-LNP (TbsAb-LNP) platform simultaneously binding LNP polyethylene glycol motifs and desired cell surface markers. By colocalizing TbsAb-LNP complexes with desired cell surface markers, we enable mRNA-LNP accumulation in the desired cell types. We additionally assessed the endosomal efficiency kinetics of TbsAb-LNP complexes generated at various bispecific loading ratios in a Galectin-9 in vitro expression model. Leveraging this facile and modular platform that eliminates the need for complex chemical conjugation approaches, we successfully achieved targeted LNP delivery to xhuCD3-expressing lymphoblasts and xmTfR1-expressing cell lines in vitro as well as xmTfR1-expressing cells in vivo. Enrichment of TbsAb-LNPs to splenic cells demonstrates the potential utility of this platform for clinical vaccine and T-cell delivery applications.