Endothelium-targeted myc silencing suppresses pathological ocular neovascularization

Ocular neovascularization (NV) causes blindness, yet anti-VEGF therapy has limited efficacy. Myc controls endothelial cell (EC) proliferation and activation, however, its pathological role in ocular NV and therapeutic value remain unclear. In this study, we found that Myc was markedly upregulated in neovascular ECs (NV-ECs). Mechanistically, glycolytic reprogramming drove the hexosamine biosynthetic pathway (HBP), promoting Myc O-GlcNAcylation, which stabilized Myc protein. Endothelial-specific Myc knockout significantly suppressed EC proliferation, thereby alleviating NV progression and preserving visual function. To target Myc therapeutically, we engineered an endothelium targeted, cell membrane hybridized lipid nanoparticle encapsulating Myc siRNA (Lip@siMyc). This system achieved homotypic targeting, vitreal penetration, and sustained Myc gene silencing, and markedly inhibited ocular NV in mice. Notably, Lip@siMyc showed efficacy comparable to aflibercept, and combined treatment produced enhanced anti angiogenic effects. In summary, our findings establish the glycolysis/HBP/Myc axis as a critical regulator of EC proliferation and highlight endothelial Myc blockade as a promising therapeutic strategy for ocular NV.