DNA Framework-EnabledOcular Barrier Penetration forMicroinvasive Antiangiogenic Therapy

Therapeutic aptamers targeting vascular endothelial growth factor A (VEGFA) have advanced the development of antiangiogenic drugs for treating choroidal neovascularization (CNV) diseases. However, despite FDA approval for use in neovascular age-related macular degeneration (nAMD), the effective <i>in vivo</i> delivery of therapeutic aptamers is hindered by ocular barriers and rapid degradation in biofluids. Here, we demonstrated a microinvasive delivery of VEGFA-targeted aptamers to the ocular fundus using tetrahedral framework nucleic acids (tFNAs). Upon incorporating anti-VEGFA aptamers to the tFNAs (apt-tFNA), we interrogated their penetration across the outer blood–retinal barrier (oBRB) to the innermost retinal in the eyeball, while maintaining their structural integrity. In addition, the apt-tFNA showed superior efficacy in inhibiting vascular proliferation and migration by neutralizing VEGFA. Furthermore, in a laser-induced CNV mouse model, subconjunctival injection of apt-tFNA exhibited comparable antiangiogenic efficacy to intravitreal ranibizumab, a monoclonal antibody fragment. These findings suggest that FNAs can effectively deliver therapeutic aptamers to the ocular fundus without compromising their antiangiogenic properties, highlighting their potential for microinvasive and feasible periocular administration in treating neovascular ophthalmic diseases.