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Peptide codes for organ-selective mRNA delivery

ABSTRACT: Organ-selective delivery of messenger RNA (mRNA) is critical for fulfilling the therapeutic potential of mRNA-based gene and protein replacement technologies. Despite clinical advances in hepatic delivery of mRNA using lipid nanoparticles (LNPs), strategies for extrahepatic organ-selective mRNA delivery remain underexplored. Here, we report a strategy, termed peptide-encoded organ-selective targeting (POST), that allows digital programming of LNPs, through surface engineering with specific amino acid sequences (POST codes), to deliver mRNA to extrahepatic organs after intravenous administration. Our molecular dynamics simulations also suggest the optimized fracture mechanics of peptide-protein assembly as a mechanism underlying sequence-dependent association between POST code and potentially organ-targeting corona proteins. POST codes are also compatible with organ-selective delivery of different ribonucleic acids and multiple gene editing machineries. This “POST code” platform presents a theoretically unlimited modular repertoire for LNP surface engineering for directing organ-tropism, thereby providing opportunities to broaden the scope and versatility of organ-selective mRNA delivery.

ORGANISM(S): Mus Musculus

SUBMITTER: Yue Shao

PROVIDER: PXD043932 | iProX | Thu Jul 20 00:00:00 BST 2023

REPOSITORIES: iProX

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