The study demonstrates that small interfering RNA (siRNA) can suppress choroidal neovascularization (CNV) in mice without targeting specific genes, through a mechanism involving toll-like receptor 3 (TLR3). Non-targeted and targeted siRNAs, including those targeting non-mammalian genes, non-expressed genes, non-genomic sequences, pro- and anti-angiogenic genes, and RNAi-incompetent siRNAs, all effectively inhibited CNV. This effect was mediated by TLR3, its adaptor TRIF, and the induction of interferon-γ and interleukin-12. The minimum length of siRNA required to suppress CNV was found to be 21 nucleotides, which forms a 2:1 complex with TLR3. The study also highlights the potential clinical implications of siRNA therapy for angiogenic disorders, suggesting that generic siRNAs might be effective in treating conditions affecting 8% of the global population.The study demonstrates that small interfering RNA (siRNA) can suppress choroidal neovascularization (CNV) in mice without targeting specific genes, through a mechanism involving toll-like receptor 3 (TLR3). Non-targeted and targeted siRNAs, including those targeting non-mammalian genes, non-expressed genes, non-genomic sequences, pro- and anti-angiogenic genes, and RNAi-incompetent siRNAs, all effectively inhibited CNV. This effect was mediated by TLR3, its adaptor TRIF, and the induction of interferon-γ and interleukin-12. The minimum length of siRNA required to suppress CNV was found to be 21 nucleotides, which forms a 2:1 complex with TLR3. The study also highlights the potential clinical implications of siRNA therapy for angiogenic disorders, suggesting that generic siRNAs might be effective in treating conditions affecting 8% of the global population.