Lipid-stabilized ICG nanoaggregates for the photodisruption of vitreous opacities

Collagen aggregation in the vitreous is a major cause of vision impairment. Current treatments such as vitrectomy or YAG laser vitreolysis remain limited by invasiveness and safety concerns. In previous work, we introduced a novel approach combining indocyanine green (ICG) with nanosecond laser pulses to achieve photodisruption of collagen aggregates via vapor nanobubbles (VNBs), while using a significantly lower total light dose than that applied in clinical laser vitreolysis. However, despite its clinical approval, free ICG poses a risk of retinal toxicity. In this work, we report the development of ICG nanoaggregates (ICG AGG NPs) stabilized with a minimal amount of a hyaluronic acid (HA)-lipid (DOPE) conjugate designed to limit retinal penetration of ICG while preserving efficient VNB generation and collagen aggregate disruption. We demonstrate that supramolecular aggregation is a key requirement for efficient VNB generation, whereas encapsulation of ICG in conventional liposomes impairs this process. Using a newly established in vitro model for quantifying collagen disruption, we show that ICG AGG NPs significantly enhance photodisruption compared to free ICG. Moreover, <i>ex vivo</i> penetration studies in bovine retinal explants reveal that ICG AGG NPs exhibit limited retinal penetration, supporting their improved ocular safety profile. In vitro cell toxicity assays on retinal pigment epithelium (RPE) and Müller cells also indicate that ICG AGG NPs maintain an acceptable safety profile at therapeutic concentrations. These findings represent the first successful demonstration of dye-loaded nanoparticles enabling efficient VNB-mediated photodisruption of vitreous opacities and highlight the promise of ICG AGG NPs as a safer and more effective alternative to free ICG for floater treatment.