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Abstract The present study investigates the potential role of dioscin (DIO) in the lipopolysaccharide (LPS)‐induced kidney injury. For this purpose, DIO‐loaded zein nanoparticles (DIO‐ZNPs) were formulated and evaluated for physicochemical parameters. The DIO‐ZNPs exhibited a controlled release of drug compared with that of the free drug suspension. Results showed that the cell viability of NRK‐52E consistently decreased with the increase in LPS from 0.01 µg/ml to 2 µg/ml. When compared with LPS, DIO‐induced NPs showed 1.10‐, 1.32‐, 1.57‐ and 1.92‐fold increase in the cell viability for concentrations of 20 µg/ml, 50 µg/ml, 100 µg/ml and 200 µg/ml, respectively. DIO‐ZNPs exhibited the most remarkable recovery in the cell proliferation compared with free DIO as shown by the cellular morphology analysis. Furthermore, Annexin‐V staining analysis showed that the LPS‐treated cells possess the lowest green fluorescence indicating fewer viable cells, whereas DIO‐ZNPs exhibited the maximum green fluorescence comparable with that of the non‐treated cells indicating maximum cell viability. Furthermore, the results show that DIO‐ZNPs significantly increased the expression of miR‐let‐7i in the epithelial kidney cells, whereas the expression levels of TLR4 were significantly downregulated compared with that of the LPS‐treated cells. In conclusion, miR‐let‐7i could be an interesting therapeutic target and nanoparticle‐based DIO could be a potential candidate in the management of acute kidney injury