Trojan Horse‐Inspired Biomimetic Lipoprotein Nanocarrier for Noninvasive Anti‐VEGF Therapy of Ocular Fundus Neovascularization

Pathological neovascularization is a major cause of vision loss in various ischemic and inflammatory ocular fundus diseases, with current anti-VEGF therapies requiring invasive and frequent intravitreal injections. In this study, a Trojan horse-inspired biomimetic lipoprotein nanocarrier (A-PA-αCPP) is developed for noninvasive anti-VEGF therapy via topical administration. Utilizing phosphatidic acid (PA), specifically 1,2-dioleoyl-sn-glycero-3-phosphate (DOPA), as the sole phospholipid, the nanocarrier enables electrostatic tethering of aflibercept, with a cell-penetrating peptide (CPP)-functionalized apoA1 mimetic peptide (αCPP) incorporated through self-assembly. Molecular dynamics simulations and intermolecular interaction experiments confirm effective PA-protein interactions and αCPP incorporation. The nanocarrier demonstrates high encapsulation efficiency, size uniformity, and long-term stability. It enhances transcellular and paracellular transport by promoting cellular uptake, bypassing lysosomal degradation, and modulating tight junctions. When topically administered, A-PA-αCPP efficiently delivers to the posterior segment via corneal and conjunctival-scleral-choroidal pathways. In a laser-induced choroidal neovascularization (CNV) mouse model, A-PA-αCPP eye drops show therapeutic efficacy comparable to a single intravitreal injection, while maintaining excellent ocular and systemic biocompatibility. This biomimetic platform highlights the potential of PA-mediated protein binding in nanocarrier design, offering a promising strategy for home-based anti-VEGF therapy and extending the potential to other protein-based therapeutics.