Peptide-guided lipid nanoparticles deliver mRNA to the neural retina of rodents and nonhuman primates

Lipid nanoparticle (LNP)-based mRNA delivery holds promise for the treatment of inherited retinal degenerations. Currently, LNP-mediated mRNA delivery is restricted to the retinal pigment epithelium (RPE) and Muller glia. LNPs must overcome ocular barriers to transfect neuronal cells critical for visual phototransduction, the photoreceptors (PRs). We used a combinatorial M13 bacteriophage-based heptameric peptide phage display library for the mining of peptide ligands that target PRs. We identified the most promising peptide candidates resulting from in vivo biopanning. Dye-conjugated peptides showed rapid localization to the PRs. LNPs decorated with the top-performing peptide ligands delivered mRNA to the PRs, RPE, and Muller glia in mice. This distribution translated to the nonhuman primate eye, wherein robust protein expression was observed in the PRs, Muller glia, and RPE. Overall, we have developed peptide-conjugated LNPs that can enable mRNA delivery to the neural retina, expanding the utility of LNP-mRNA therapies for inherited blindness.

Automated summary

Lipid nanoparticle (LNP)-based mRNA delivery shows promise for treating inherited retinal degenerations. By using a peptide phage display library, we identified promising peptide ligands for targeting photoreceptors (PRs). Dye-conjugated peptides quickly localized to PRs and LNPs decorated with these peptides successfully delivered mRNA to PRs, RPE, and Muller glia in mice and nonhuman primates. This development expands the application of LNP-mRNA therapies for inherited blindness by enabling mRNA delivery to the neural retina.