Acid-responsive lipid-coated CaCO3/Cisplatin "Watermelon-shaped" nanoparticles combined with Bmi1 siRNA reverse HCC resistance by inhibiting cancer stem cells

Abstract

Abstract Cisplatin resistance is a major obstacle in the treatment of Hepatocellular carcinoma (HCC), characterized by reduced intracellular drug accumulation and altered DNA repair/apoptosis signaling. Current strategies targeting individual factors have limited efficacy in reversing cisplatin resistance. To address this challenge, we propose a novel drug delivery system utilizing watermelon-shaped nanoparticles composed of a cisplatin core evenly distributed within a CaCO3 shell. These nanoparticles are subsequently coated with positively charged phospholipids, facilitating the absorption of Bmi1 siRNA (LCa/C@B) with the ability to inhibit HCC cancer stem cells (CSCs). In vitro and in vivo experiments demonstrate the effective release of Bmi1 siRNA and cisplatin in the slightly acidic tumor microenvironment, resulting in their uptake by drug-resistant tumor cells. LCa/C@B exhibits a synergistic effect in inhibiting CSCs, effectively reversing cisplatin chemotherapy resistance, and improving the therapeutic outcomes in HCC-resistant cells and an HCC primary mouse model. This hybrid drug delivery system, combining calcium carbonate and cisplatin with Bmi1 siRNA, presents a promising approach for overcoming chemotherapy resistance in HCC.