Small interfering RNA (siRNA) targeting vascular endothelial growth factor-A (VEGFA) or its receptor VEGFR1 suppresses choroidal neovascularization (CNV) in age-related macular degeneration (AMD) through a sequence- and target-independent mechanism involving toll-like receptor 3 (TLR3). This study demonstrates that siRNAs, regardless of sequence, target, or internalization efficiency, can suppress CNV in mice by activating TLR3, leading to the production of interferon-γ and interleukin-12. The effect is independent of RNA interference (RNAi) and does not involve interferon-α/β activation. Non-targeted siRNAs, which do not target mammalian genes, also suppress CNV through TLR3, indicating a broad anti-angiogenic effect. The minimum length of siRNA required for TLR3 activation is 21 nucleotides, as shorter sequences fail to activate TLR3. The study also shows that siRNAs targeting non-mammalian genes or non-expressed genes can suppress CNV as effectively as those targeting VEGFA or VEGFR1. Additionally, the study highlights the importance of TLR3 in the anti-angiogenic effect of siRNAs, with TLR3-deficient mice showing reduced CNV suppression. The findings suggest that siRNAs can be used as a generic therapy for angiogenic disorders, including AMD, and that TLR3 activation may be a key mechanism for this effect. The study also discusses the implications of these findings for clinical applications, including the potential for personalized pharmacogenetic therapy based on TLR3 genotypes.Small interfering RNA (siRNA) targeting vascular endothelial growth factor-A (VEGFA) or its receptor VEGFR1 suppresses choroidal neovascularization (CNV) in age-related macular degeneration (AMD) through a sequence- and target-independent mechanism involving toll-like receptor 3 (TLR3). This study demonstrates that siRNAs, regardless of sequence, target, or internalization efficiency, can suppress CNV in mice by activating TLR3, leading to the production of interferon-γ and interleukin-12. The effect is independent of RNA interference (RNAi) and does not involve interferon-α/β activation. Non-targeted siRNAs, which do not target mammalian genes, also suppress CNV through TLR3, indicating a broad anti-angiogenic effect. The minimum length of siRNA required for TLR3 activation is 21 nucleotides, as shorter sequences fail to activate TLR3. The study also shows that siRNAs targeting non-mammalian genes or non-expressed genes can suppress CNV as effectively as those targeting VEGFA or VEGFR1. Additionally, the study highlights the importance of TLR3 in the anti-angiogenic effect of siRNAs, with TLR3-deficient mice showing reduced CNV suppression. The findings suggest that siRNAs can be used as a generic therapy for angiogenic disorders, including AMD, and that TLR3 activation may be a key mechanism for this effect. The study also discusses the implications of these findings for clinical applications, including the potential for personalized pharmacogenetic therapy based on TLR3 genotypes.