Biological barriers to lipid nanoparticle mediated messenger RNA delivery to the retina

Lipid nanoparticle (LNP) mediated messenger RNA delivery to the retina has potential to treat a variety of retinal disorders by the transient expression of proteins, benefitting those applications that require short-term intracellular protein expression such as reprogramming or genome editing. Efficient delivery of mRNA to the retina remains however a major bottleneck. In short, LNPs should encapsulate sufficient amounts of mRNA, protect mRNA against degradation, be mobile in the vitreous and migrate over the inner limiting membrane (ILM) to reach the retinal cells. Furthermore, LNPs should be taken up in the desired cell type and avoid immune recognition during all steps of the delivery pathway. This lecture will discuss several extracellular and intracellular barriers encountered after intravitreal injection of LNPs and the ex vivo models that were developed to study them.