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

Abstract

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 Müller 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 Müller glia in mice. This distribution translated to the nonhuman primate eye, wherein robust protein expression was observed in the PRs, Müller 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.

Next-generation materials for RNA–lipid nanoparticles: lyophilization and targeted transfection

“…Herrera-Barrera et al identified peptides, which target PRs by utilizing a combinatorial M13 bacteriophage-based heptameric peptide phage display library. 76 The peptide, they found, SPALHFL, showed immediate localization to the PRs. Therefore, they prepared RNA-LNPs conjugated with the peptide, which successfully could deliver mRNA into RPE, Mu ¨ller glia, and PRs in mice and nonhuman primate, where LNPs were consisted of DMG-PEG2000, DSPC, cholesterol, and DLin-MC3-DMA as well as DSPE-PEG2000-conjugated MH43 peptide (SPALHFL-GGGSC).…”

“…RNA-LNPs and other drugs typically accumulate in liver cells upon intravenous administration. 66 Several LNPs have been developed for the delivery of LNPs into targeted tissues by different administration routes in vivo, 48,[67][68][69][70][71][72] by adapting the specific lipid composition, 73,74 and by the addition of specific peptides, 55,[74][75][76] aptamers, 77 and ligands (Fig. 4).…”

“…Currently, RNA-LNP delivery is restricted to the Mu ¨ller glia or retinal pigment epithelium (RPE). 76 RNA-LNPs need to pass ocular barriers for transfection of neuronal cells, which are important for visual phototransduction of the photoreceptors (PRs). Herrera-Barrera et al identified peptides, which target PRs by utilizing a combinatorial M13 bacteriophage-based heptameric peptide phage display library.…”

“…Therefore, they prepared RNA-LNPs conjugated with the peptide, which successfully could deliver mRNA into RPE, Mu ¨ller glia, and PRs in mice and nonhuman primate, where LNPs were consisted of DMG-PEG2000, DSPC, cholesterol, and DLin-MC3-DMA as well as DSPE-PEG2000-conjugated MH43 peptide (SPALHFL-GGGSC). 76 The peptide, GGGSC, was used as a joint segment to bind DSPE-PEG2000 and MH43 peptide. They developed specific peptide-conjugated RNA-LNPs that can enable mRNA delivery to the neural retina (PRs), which can expand the utility of mRNA-LNP therapies for inherited blindness of patients in future.…”

Analysis of PEG-lipid anchor length on lipid nanoparticle pharmacokinetics and activity in a mouse model of traumatic brain injury

“…While viral vectors are highly efficient, LNPs are a potential alternative that have lower immunogenicity 7 and are less limited by cargo size. 8,9 In addition, the activity of LNPs is more transient compared to viral vectors, [10][11][12][13] making them well-matched to treat the acute phase of TBI within days to weeks of the injury. [14][15][16] LNPs are currently the most clinically advanced non-viral gene delivery vehicle, and multiple formulations have been approved by the FDA.…”