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Hepatocellular carcinoma(HCC)，one o f the most common cancers worldwide,is the second leading cause o f cancer related deaths throughout the world.Despite the latest advancement in medicine and treatment techniques,HCC incidences are increasing constantly for the past40years world-wide.Chemotherapy is being considered as a primary treatment choice against HCC,with cisplatin(CDDP)，a widely used chemotherapeutic agent against hepatocellular carcinoma(HCC),faces severe resistance and hepatotoxicity problems which can be alleviated through combination therapy.In this study，we have developed a pH-dependent calcium carbonate nano-delivery system for the combination therapy o f CDDP with oleanolic acid(OA).A microemulsion method was employed to generate CDDP and OA-lipid coated calcium carbonate nanoparticles(CDDP/OA-LCC NPs),having optimized uniform size distribution with an average particle size o f206士15nm and63.70士3.9%entrapment efficiency.The amount of lipids,Ca2+/C032"and surfactants in the developed nanoparticles were optimized via hit and trail method with its net effect on the particle sizes and entrapment efficiency were taken into consideration.In vitro drug release study confirmed the pH dependent property o f calcium carbonate in the formulation,with the maximum CDDP release o f70土4.6%at acidic pH range,in contrast to28士4.1%CDDP release at basic pH.However，there were no significant differences observed in the O A release at different pH conditions.In-vitro HepG2cells internalization study conducted via a fluorescent coumarin-6(C-6)loaded nanoparticle(C-6LCC NPs)demonstrated the greater localization o f the nanoparticles around the cell nuclei with the passage o f time,confirming the greater potential o f our delivery vehicle in loaded drugs transportation and tumor targeting.Annexin V-FITC/PI assay and DAPI staining assay confirmed that CDDP and OA synergistically promoted the HepG2cells apoptosis for the CDDP/OA-LCC NPs,presented far greater apoptosis in the combination therapy treatedIn conclusion,CDDP/OA-LCC NPs with promising features and beneficial aspects as far as its characterization,cytotoxicity,cellular uptake,safety and efficacy evaluation aspects are concerned,making it an ideal carrier for co-delivering CDDP and OA,to synergize their anti-tumor activity against HCC and to utilize OA’s protective effect against CDDP induced hepatotoxicity.