Antibody targeted delivery of lipid nanoparticles for RNA therapeutics to immune cells

Despite the successful development of RNA therapeutics (mRNA and RNAi) with lipid nanoparticles (LNP) delivery in site-specific organs, this underscores the need for precise targeting. The manipulation of LNP through the attachment of moieties, including small molecules, cell-penetrating peptides (CPP), aptamers, and monoclonal antibodies (mAb), using click chemistry, has shown promising results in enhancing the efficacy of targeted RNA therapy. mAbs play a predominant role in targeted therapy due to controllability (the number and orientation of mAb conjugated to each LNP), stability, reliability, reproducibility, and well-validated (covalent) conjugation. Additionally, the advancement of covalent conjugation using PEGylated lipids with biochemical linkers has resulted in the establishment of techniques for selectively transfecting lymphocytes, which are typically challenging to transfect. This approach also enables conformation-sensitive targeting of specific antigen (AGN). The body of this research is based on the design description of modular targeting platforms with a focus on the development of chemical moieties and genetic recombination agents for T and B cells, dendritic cells (DC), monocytes (MCY), and macrophages (MPG). Furthermore, the mechanism (direct and indirect) and attachment orientation of all used mAb-lipid moieties on LNP were discussed in detail. Finally, the recent advances and pros and cons of targeted RNA therapeutics using mAb-LNP for the immune cells were explored.