Targeted degradation of VEGFR2 via PROTAC encapsulated by cRGD-liposome reverses pathological corneal neovascularization.

Abstract

Vascular endothelial growth factor receptor 2 (VEGFR2) is a pivotal regulator of angiogenesis, rendering it a key therapeutic target for pathological neovascularization. Here, PROTAC-V2 (V2), a potent proteolysis-targeting chimera for targeting VEGFR2 degradation, is utilized. To overcome pharmacological barriers like poor aqueous solubility and limited ocular surface bioavailability, a cyclic RGD (cRGD) peptide-functionalized liposomal delivery system (cRGD Liposome) is engineered. Liposomes were strategically selected as the nanocarrier due to their exceptional biocompatibility and established record as the most successful class of FDA-approved nanomedicines. The nano-formulation, cRGD-LNP@V2, successfully encapsulated the hydrophobic degrader within its lipid bilayer, featuring a suitable particle size. This biomimetic platform leverages cRGD-mediated targeting of αvβ3 integrins to facilitate site-specific accumulation and catalytic VEGFR2 ablation at the site of pathological neovascularization. Consequently, driven by enhanced intracellular delivery rather than an intrinsic increase in molecular potency, cRGD-LNP@V2 exhibited markedly improved apparent potency in vitro, achieving a VEGFR2 IC₅₀ of 4.78 μM. This enhanced activity translated directly to superior therapeutic efficacy in vivo, where cRGD-LNP@V2 demonstrated profound inhibition of disease progression in both suture-induced and alkali-burn mouse models of corneal neovascularization (CoNV). By integrating active targeting, enhanced drug delivery, and catalytic protein degradation, cRGD-LNP@V2 represents a significant therapeutic advancement that effectively overcomes the limitations of conventional inhibitors, establishing a potent paradigm for treating neovascular diseases.