Nanomaterial-Based Anti-Angiogenic Gene Therapy for Retinal Neovascular Diseases: Mechanistic Insights and Preclinical Advances.

Retinal neovascular diseases (RNVs) are the leading cause of preventable vision loss worldwide, including diabetic retinopathy, age related macular degeneration, retinopathy of prematurity, and retinal vein occlusion. Anti-VEGF therapy remains central to current clinical management, while emerging molecular targets, including ANG-2, PDGF, Sema4D, integrins, and inflammatory mediators, are gaining therapeutic relevance. The current standard anti-VEGF intravitreal injection (administered every 4-8 weeks) regimen significantly increases the risk of complications such as endophthalmitis and elevated intraocular pressure, which has driven interest in one-time gene therapy approaches. However, traditional viral delivery systems for gene therapy are limited by limited drug loading and poor biocompatibility. This review systematically investigated nanomaterial mediated gene therapy options for anti-angiogenesis in RNVs, focusing on six distinct nanomaterial categories: metal nanoparticles, carbon/silicon nanostructures, lipid nanoparticles, polymers, dendrimers, and nanocomposites. The advantages and limitations of various nanomaterials in terms of gene-loading capacity, controlled release profiles, biocompatibility, and transfection efficiency in the preclinical application of anti-angiogenic gene therapy for RNV diseases were compared. It also provides unique insights into the future multi-target therapy of nanomaterials and hybrid nanomaterial delivery.