**4. Conclusions**

Targeting of angiogenesis by means of RNA interference is a promising and highly necessary approach for treatment of angiogenesis-related diseases induced by abnormally stimulated neovascularization such as cancer, atherosclerosis, age-related macular degeneration, endometriosis, etc. However, the need for efficient and specific siRNA delivery systems is of importance for the development of this promising approach. The efficiency of an anti-angiogenic treatment can be further improved via the combinatorial delivery of siRNAs against multiple pro-angiogenic targets. Here, we have demonstrated the efficient down-regulation of endothelial cells migration and proliferation by anti-VEGFA, anti-VEGFR1, and anti-Endoglin siRNA delivery mediated by peptide-based vector L1. Several types of single and combinatorial L1-based siRNA polyplexes have been studied and the most efficient formulation has been found. Based on our findings, we have concluded that a combinatorial treatment by L1-polyplexes formed with anti-VEGFA and anti-VEGFR1 siRNAs effectively inhibits migration and proliferation of endothelial cells and can be suggested as a useful tool for anti-angiogenic therapy.

**Author Contributions:** A.V.K., D.I.S., and A.A.E. designed the work; A.A.E., M.A.M., and S.V.S. performed the transfection experiments; A.A.E. and S.V.S. performed the genes expression analysis; A.A.E., M.A.M., and S.V.S. performed the functional cytological experiments; A.V.K. and A.A.E. analyzed the data; S.A.S. and V.S.B. provided funding acquisition and conceptualization of the work; S.A.S. and A.V.K. supervised the work, A.A.E. prepared the original draft; A.V.K. and D.I.S.performed the review and editing of the manuscript, and all other authors revised it critically.

**Funding:** This research was funded by the Russian Science Foundation, grant number 17-15-01230 (transfection/migration and proliferation studies of endothelial cells) and by the Ministry of Science and Higher Education of the Russian Federation, project number AAAA-A19-119021290033-1 (gene expression analysis and transfection studies of cancer cells). M.A.M. is supported by a President of Russian Federation scholarship (SP-822.2018.4).

**Acknowledgments:** Authors express their gratitude to Ksenia Markova and Anastasia Kozyreva for their assistance in the endothelial cell culturing.

**Conflicts of Interest:** The authors declare no conflict of interest.
