Background/Objectives: Cisplatin remains a cornerstone chemotherapeutic agent for non-small-cell lung cancer (NSCLC) treatment, yet its clinical utility is substantially limited by acquired resistance and the inadequate suppression of tumor metastasis. Emerging evidence implicates interleukin 6 (IL-6) as a critical mediator of chemoresistance through cancer stem cell (CSC) enrichment and metastasis promotion via epithelial–mesenchymal transition (EMT) induction, ultimately contributing to cisplatin therapy failure. This study sought to address these challenges by designing a nanoplatform with two innovative aims: (1) to achieve active tumor targeting through binding to the IL-6 receptor (IL-6R), and (2) to concurrently inhibit IL-6-mediated chemoresistance signaling pathways. Methods: A lipid–polymer hybrid nanoparticle (LPC) encapsulating cisplatin was synthesized and subsequently surface-functionalized with tocilizumab (TCZ), a monoclonal antibody that targets IL-6R. The therapeutic efficacy of this TCZ-modified nanoparticle (LPC-TCZ) was assessed through a series of in vitro and in vivo experiments, focusing on the inhibition of EMT, expression of CSC markers, tumor growth, and metastasis. Results: Systematic in vitro and in vivo evaluations revealed that LPC-TCZ synergistically attenuated both EMT progression and CSC marker expression through the targeted blockade of IL-6/STAT3 signaling. This multimodal therapeutic strategy demonstrated superior tumor growth inhibition and metastatic suppression compared to conventional cisplatin monotherapy. Conclusions: Our findings establish a nanotechnology-enabled approach to potentiate cisplatin efficacy by simultaneously countering chemoresistance mechanisms and metastatic pathways in NSCLC management.

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.

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.