Combined inhibition of CD73 and ZEB1 by Arg-Gly-Asp (RGD)-targeted nanoparticles inhibits tumor growth

•RGD-modified chitosan lactate nanoparticles exhibited high cellular uptake and permeability•ZEB-1 and CD73-siRNA loaded RGD-CL NPs efficiently downregulate CD73/ZEB-1 expression.•Simultaneous suppression of CD73/ZEB-1 reduces cancer cell invasion and proliferation.•The Co-inhibition of CD73/ZEB-1 decreases tumor volume in vivo. Abnormal expression of several macromolecules within tumor milieu helps the development of neoplasia and immune suppression in various cancers. ZEB-1 and CD73 are important factors in tumor progression, which their overexpression in tumor site enhances several cancer hallmarks, including proliferation, angiogenesis, metastasis, migration, and invasion. In this study, we decided to inhibit the expression of these factors in the tumor site by using RGD-conjugated chitosan lactate (RGD-CL) nanoparticles (NPs) encapsulating CD73/ZEB-1 siRNA molecules, in vitro and in vivo. The NPs were about 127 nm in size, non-toxic, and RGD conjugation to NPs could efficiently increase cell transfection through interaction with αvβ3 integrins expressed on cancer cells and tumoral endothelial cells.Moreover, RGD-conjugated CL NPs containing siRNAs could significantly reduce the ZEB-1 and CD73 expression levels in cancer cells. Following transfection, cancer cells showed a significant reduction in migration and proliferation. Furthermore, the administration of these NPs into 4T1 and CT26 tumor-bearing mice resulted in tumor suppression and prolonged survival. These findings indicate the importance of targeting the CD73/ZEB1 axis in cancer cells, which could encourage their use in cancer patients in the near future.