Targeted mRNA delivery with bispecific antibodies that tether LNPs to cell surface markers
Bettina Dietmair, James Humphries, Tim R. Mercer, Kristofer J. Thurecht, Christopher B. Howard, Seth W. Cheetham
Abstract
Efficient delivery of mRNA-lipid nanoparticles (LNPs) to specific cell types remains a major challenge for mRNA therapeutics. Conventional targeting approaches involve modifying the lipid composition or functionalizing the surface of LNPs, which complicates manufacturing and alters nanoparticle size, charge, and stealth, impacting their delivery and immunogenicity. Here, we present a generalizable method for targeted mRNA-LNP delivery that uses bispecific antibodies (BsAbs) to form a bridge between LNPs and cell surface markers. BsAbs can be combined with LNPs or administered first, binding to surface proteins on target cells and later retaining unmodified LNPs in affected tissues. We demonstrate the efficient and cell-type-specific delivery of mRNA-LNPs beyond the liver, targeting epidermal growth factor receptor (EGFR)- and folate hydrolase 1 (PSMA)-positive cells <i>in vitro</i> and <i>in vivo</i>. The flexibility of this technology, achieved by substituting the cell-targeting region of the BsAbs, enables the rapid development of next-generation targeted mRNA drugs.