Chemotherapy is the most common therapeutic strategy for the treatment of unresectable hepatocellular carcinoma. However, the therapeutic efficacy is limited by low delivery efficiency of chemotherapeutics and severe toxicity towards healthy tissues. To address the challenges, an active-targeting mesoporous silica nanoparticles conjugating platinum(IV) prodrug was developed for liver cancer therapy for the first time. Taking advantage of liver-targeting lactobionic acid (LA), the smart nano-carriers could not only enhance the circulation time but also effectively concentrate at liver tumor site. Moreover, the conjugated Platinum(IV) could be reduced in tumor reductive environment for fast releasing of active platinum(II). The novel targeting and self-responsive drug-loading system brings a new prospective for the liver cancer chemotherapy.