Dihydromyricetin (DHM) has garnered attention due to its promising antitumor activity, but its low bioavailability restricts its clinical application. Thus, developing nano-drug delivery systems could enhance its antitumor activity. We prepared DHM@ZIF-8 nanoparticles using the zeolite imidazole framework-8 (ZIF-8) as a carrier loaded with dihydromyricetin. A series of characterizations were performed, including morphology, particle size, zeta potential, X-single crystal diffraction, ultraviolet spectroscopy, infrared spectroscopy, and Brunauer–Emmett–Teller (BET). The in vitro release characteristics of DHM@ZIF-8 under pH = 5.0 and pH = 7.4 were studied using membrane dialysis. The antitumor activity and pro-apoptotic mechanism of DHM@ZIF-8 were investigated through CCK-8 assay, reactive oxygen species (ROS), Annexin V/PI double-staining, transmission electron microscopy, and Western blot. The results depicted that DHM@ZIF-8 possessed a regular morphology with a particle size of 211.07 ± 9.65 nm (PDI: 0.19 ± 0.06) and a Zeta potential of −28.77 ± 0.67 mV. The 24 h drug releasing rate in PBS solution at pH = 7.4 was 32.08% and at pH = 5.0 was 85.52% in a simulated tumor micro acid environment. DHM@ZIF-8 could significantly enhance the killing effect on HepG2 cells compared to the prodrug. It can effectively remove ROS from the tumor cells, promote apoptosis, and significantly affect the expression of apoptosis-related proteins within tumor cells.

In this study, we designed and developed a DOX nanodrug delivery system (PEG-GA@ZIF-8@DOX) using ZIF-8 as the carrier and glycyrrhetinic acid (GA) as the targeting ligand. We confirmed that DOX was loaded and PEG-GA was successfully modified on the surface of the nanoparticles. The in vitro release profile of the system was investigated at pH 5.0 and 7.4. The cellular uptake, in vitro cytotoxicity, and lysosomal escape characteristics were examined using HepG2 cells. We established an H22 tumor-bearing mouse model and evaluated the in vivo antitumor activity. The results showed that the system had a uniform nanomorphology. The drug loading capacity was 11.22 ± 0.87%. In acidic conditions (pH 5.0), the final release rate of DOX was 57.73%, while at pH 7.4, it was 25.12%. GA-mediated targeting facilitated the uptake of DOX by the HepG2 cells. PEG-GA@ZIF-8@DOX could escape from the lysosomes and release the drug in the cytoplasm, thus exerting its antitumor effect. When the in vivo efficacy was analyzed, we found that the tumor inhibition rate of PEG-GA@ZIF-8@DOX was 67.64%; it also alleviated the loss of the body weight of the treated mice. This drug delivery system significantly enhanced the antitumor effect of doxorubicin in vitro and in vivo, while mitigating its toxic side effects.