Intravitreal anti-vascular endothelial growth factor (VEGF) therapy has fundamentally transformed the management of retinal and choroidal neovascular diseases. Despite its proven efficacy, long-term reliance on repeated intravitreal injections imposes a substantial burden on patients and healthcare systems. Real-world studies consistently demonstrate reduced adherence and inferior visual outcomes compared with randomized clinical trials. These limitations have driven interest in alternative, non-intravitreal routes of anti-VEGF delivery aimed at reducing treatment burden while maintaining therapeutic efficacy. This narrative review provides a comprehensive evaluation of suprachoroidal, systemic, transscleral, episcleral, subretinal, and topical non-intravitreal delivery strategies. Emphasis is placed on ocular pharmacokinetic barriers, pharmacodynamic requirements for sustained VEGF suppression, reasons for historical failures, and the translational maturity of emerging experimental platforms. While selected approaches, particularly suprachoroidal and gene-based strategies, show encouraging early results, intravitreal anti-VEGF therapy continues to represent the standard of care for ocular neovascular diseases.
Joshi et al. (Fri,) studied this question.