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.

许多用于治疗失明的开创性疗法需要通过玻璃体内注射将生物制剂或细胞输送到视网膜内层。不幸的是，这些疗法的进步受到递送困难的极大阻碍，其中内界膜 (ILM) 处的治疗阻塞是主要的瓶颈。在这项原理验证研究中，我们探索了一种创新的基于光的方法，以微创和高度控制的方式局部消融 ILM，从而使 ILM 对治疗更具渗透性。更具体地说，我们证明了 ILM 结合的吲哚菁绿 (ICG) 的脉冲激光照射，这是一种临床应用的 ILM 染料，会导致形成蒸汽纳米气泡，这可以破坏牛 ILM 以及非常厚的人类 ILM。我们观察到，这种光破坏允许模型纳米颗粒在视网膜上非常成功地传递，否则这些纳米颗粒会被完整的 ILM 阻止。引人注目的是，这种治疗还能够将载有 mRNA 的脂质纳米颗粒在牛视网膜内的功效提高 5 倍。总之，这项研究为克服 ILM 的基于光的方法提供了证据，该方法有可能改善所有视网膜疗法的功效都受到这种传递障碍的阻碍。