Sustained suppression of choroidal neovascularization by intraocularly stable tetrahedral network encapsulated miR-22–3p

Choroidal neovascularization (CNV), characterized by abnormal vessel growth and vascular leakage, is the hallmark of wet age-related macular degeneration (wAMD) and a leading cause of irreversible vision loss. Although anti-vascular endothelial growth factor (VEGF) therapies remain the current standard, their frequent administration and limited long-term efficacy highlight the need for novel treatments. Here, we developed a miR-22-3p-loaded tetrahedral framework nucleic acids (tFNAs-miR22) nanostructure and evaluated its efficacy in CNV suppression. The nanocomplex was structurally validated, exhibiting high assembly fidelity and superior intraocular stability compared to serum conditions. In a laser-induced CNV mouse model, a single intravitreal injection of tFNAs-miR22 significantly reduced lesion size and leakage by day 10, with efficacy comparable to aflibercept. In a rat model of stable and long-lasting CNV, tFNAs-miR22 demonstrated durable inhibition of vascular leakage by Day 21, showing greater persistence compared to aflibercept. This effect was dose-dependent, with the high-dose group outperforming aflibercept in suppressing leakage. Transcriptomic profiling of hypoxia-challenged HUVECs further revealed that tFNAs-miR22 modulates angiogenic pathways, including suppression of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) axis. These findings demonstrate the potent and long-lasting therapeutic effects of tFNAs-miR22, supporting its promise as a next-generation, gene-regulatory nanotherapy for sustained inhibition of CNV.