Engineering Concentration-Dependent Intravitreal Mobility via Cyclic Arginine-Enriched Nanocarrier Surface Modification: In Vivo Proof-of-Concept in a Porcine Large Animal Model.

Nanoparticulate drug delivery systems represent a promising platform for sustained intraocular drug release following intravitreal administration, leveraging low metabolic turnover of the vitreous to maintain therapeutic drug levels over extended periods. Despite this potential, nanoparticle diffusion toward the visual axis can induce light scattering and visual disturbance. Given the negative charge of the vitreous, surface-engineered nanoparticles provide a strategy to modulate particle mobility and restrict off-target migration. Here, we performed a 6-week in vivo evaluation in pigs of an intravitreally applied, positively charged, cyclic-arginine surface-functionalized liposomal nanocarrier designed to reduce intravitreal mobility. Three formulations containing 0.1%, 0.5%, or 1% cyclic-arginine-modified phospholipid were compared with unmodified control liposomes in a large animal pig model. A multimodal biocompatibility and performance assessment was conducted, including intraocular pressure monitoring, fundus imaging, structural and angiographic OCT, dye-based angiography, and post-mortem retinal immunostainings. Cyclic-arginine surface functionalization of the liposomes resulted in a concentration-dependent reduction in intravitreal mobility, quantified by vitreous haze and fundus-based distribution analyses. All surface-engineered nanoparticles demonstrated excellent ocular biocompatibility without structural or vascular adverse effects. These data establish cyclic-arginine surface modification as a robust design principle to modulate intravitreal mobility and support the development of next-generation nanoparticle biomaterials for long-acting ophthalmic drug delivery.