Dual-Targeting CSC Therapy: Acid-Responsive Cisplatin/CaCO3@siRNA Nanoplatform Overcomes HCC Chemoresistance

TL;DR

A new nanoplatform combining cisplatin and Bmi1 siRNA effectively overcomes chemotherapy resistance in liver cancer.

Contribution

An acid-responsive nanoplatform that delivers cisplatin and Bmi1 siRNA to combat HCC chemoresistance.

Findings

LCa/C@B enhanced cisplatin accumulation and restored chemosensitivity in resistant liver cancer cells.

In vivo experiments showed tumor growth inhibition and suppression of cancer stem cells.

The dual-targeting approach outperformed free cisplatin and single-component treatments.

Abstract

Background: 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. Methods: To address this challenge, we developed an acid-responsive nanoplatform consisting of a cisplatin-loaded CaCO3 core with a lipid coating that enables surface adsorption of Bmi1 siRNA, termed LCa/C@B. Results: These nanoparticles are subsequently coated with positively charged phospholipids, facilitating the absorption of Bmi1 siRNA. In vitro, LCa/C@B markedly enhanced intracellular cisplatin accumulation, downregulated Bmi1 and cancer stem cell (CSC) markers, and restored chemosensitivity in HepG2/MDR cells. In vivo, LCa/C@B achieved improved tumor localization, significant Bmi1 knockdown, suppression of CSC populations, and robust inhibition of tumor growth in a primary HCC model. Importantly, the dual-targeting design produced a synergistic therapeutic effect superior to free cisplatin or single-component formulations. Conclusions: This hybrid drug delivery system, combining calcium carbonate and cisplatin with Bmi1 siRNA, presents a promising approach for overcoming chemotherapy resistance in HCC.

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