ICG-mediated photodisruption of the inner limiting membrane enhances retinal drug delivery

Many groundbreaking therapies for the treatment of blindness require delivery of biologics or cells to the inner retina by intravitreal injection. Unfortunately, the advancement of these therapies is greatly hampered by delivery difficulties where obstruction of the therapeutics at the inner limiting membrane (ILM) represents the dominant bottleneck. In this proof-of-principle study, we explore an innovative light-based approach to locally ablate the ILM in a minimally invasive and highly controlled manner, thus making the ILM more permeable for therapeutics. More specifically, we demonstrate that pulsed laser irradiation of ILM-bound indocyanine green (ICG), a clinically applied ILM dye, results in the formation of vapor nanobubbles which can disrupt the bovine ILM as well as the extraordinary thick human ILM. We have observed that this photodisruption allows for highly successful retinal delivery of model nanoparticles which are otherwise blocked by the intact ILM. Strikingly, this treatment is furthermore able of enhancing the efficacy of mRNA-loaded lipid nanoparticles within the bovine retina by a factor of 5. In conclusion, this study provides evidence for a light-based approach to overcome the ILM which has the potential to improve the efficacy of all retinal therapies hampered by this delivery barrier. [Display omitted] •ICG that is accumulated at the ILM can generate vapor nanobubbles upon irradiation with pulsed laser light.•The formation and collapse of vapor nanobubbles can locally disrupt the ILM, rendering it more permeable for therapeutics.•ILM photodisruption substantially enhances delivery of 120 nm-sized polystyrene & lipid nanoparticles into the bovine retina.•ILM manipulation boosted the efficacy of mRNA-loaded lipid nanoparticles within the bovine retina by a factor of 5.•This technology is also successful in ablating the complex and extraordinary thick human ILM.