Epithelial ovarian cancer (EOC) is one of the leading malignant tumors that seriously threaten women’s health. The development of new drugs or increasing the sensitivities of current chemotherapy drugs is critically needed. The purpose of this study was to assess the synergistic effects of two silencing RNAs [salt-inducible kinase 2 (SIK2) siRNA and antisense-microRNA21 (anti-miR21)] encapsulated in long-circulating folate-lipid-poly(lactic–glycolic acid) (PLGA) hybrid nanopolymers (FaLPHNPs) administered using an ultrasound- and microbubble (US-MB)-mediated approach to sensitize human EOC xenografts to paclitaxel (PTX). In the assays, this lipid-PLGA hybrid nanopolymer exhibited an extended circulation profile (: ∼8.5 h); US-MB-mediated complementary delivery of FaLPHNPs resulted in a significant reduction in EOC cell (OVCR3, A2780, and SKOV3) proliferation. , there was a 2.5-fold increase ( < 0.05) in RNA delivery in EOC xenografts, which resulted in a notable inhibition of tumor growth compared with that in the non-ultrasound-mediated and PTX alone-treated controls. We validated the therapeutic roles of SIK2, the target gene in treating advanced ovarian cancer, and anti-miR21 by evaluating the significant inhibition of tumor growth upon SIK2 silencing and inhibition of endogenous miR21 function. In summary, the results of this study revealed that US-MB-mediated codelivery of SIK2 siRNA, and anti-miR21 encapsulated in a folate-lipid-PLGA hybrid polymer nanoparticle could significantly improve the sensitivity of EOC tumors to PTX and is a highly effective approach for treating EOC in complementary experiments. Further research of this strategy could lead to better treatment results for patients with EOC.