Balancing the antitumor activity and systemic toxicity of tripterine still faces a big challenge due to the narrow therapeutic window . To address this issue, we report a microemulsion system based on tripterine, brucea oil, and glycyrrhizin, and dual modified with both transferrin and cell-penetrating peptide SA-R6H4 (Tf/SA-R6H4-TBG-MEs) for combinational and tumor-targeted cancer therapy . Such a microemulsion exhibited a spherical shape with a size of ~50 nm and a mildly-negative charge . The half-maximal inhibitory concentration (IC50) of Tf/SA-R6H4-TBG-MEs against ovarian cancer SKOV3 cells was 0.27 ± 0.43 µg tripterine/mL, which was 5.85 times lower than that of free tripterine . The cellular uptake of tripterine after treatment with Tf/SA-R6H4-TBG-MEs was 1.56 times higher than that of TBG-MEs (non-modified microemulsion). In pharmacokinetics studies, the area under the curve of Tf/SA-R6H4-TBG-MEs increased by 1.97 times compared with that of the physical mixture group . The tumoral accumulation of tripterine was significantly improved in Tf/SA-R6H4-TBG-MEs group than TBG-MEs-treated group . In antitumor efficacy in vivo, Tf/SA-R6H4-TBG-MEs exhibited the strongest inhibition of tumor growth and the longest survival period among all the groups, which is associated with the rational combination, microemulsion system, and dual modification with tumor-targeted ligands . Importantly, Tf/SA-R6H4-TBG-MEs significantly reduced the toxicity of tripterine against the liver and kidney . Our design provides a new approach for efficient and safe ovarian cancer therapy based on a multicomponent combination.