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

Abstract 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.