INTRODUCTION: Intensive cancer treatment with nanoplatform is widely exploited in the clinic, the emerging nanomedicine offers an unparalleled opportunity for encapsulating potential antitumor drugs in a nano-carrier. Apoptin (AP), a coding protein of VP3 gene, stem from the chicken anemia virus (CAV), can be activated in malignant cells selectively and prevents the dividing cancer cells from repairing their DNA lesions, thereby forcing them to undergo apoptosis. Herein, a three-step intelligent biodegradable drug delivery nanoplatform was designed. METHODS: First, a hollow ZIF-8 was synthesized, embedded with platinum nanoparticle to form ZIF-8, and then loaded with AP, and lastly formed AP@ZIF-8, which possess pH-responsive drug release and cancer-targeted ability. RESULTS: As expected, both in vitro and in vivo experiment demonstrated that AP@ZIF-8 performed treatment effects in hepatocarcinoma through relieving tumor-hypoxic microenvironment, inhibiting cell proliferation and promoting cell apoptosis. Further transcriptomic analysis showed that the specific mechanism of the AP@ZIF-8 was thermogenesis, signaling pathways regulating pluripotency of stem cells, ribosome, prion disease and PI3K-Akt signaling pathway. DISCUSSION: This work highlights a new strategy for liver cancer treatment and provides a reference for treating malignant tumors.