Multifunctional ginsenoside Rg3-integrated liposomes for synergistic chemo-photothermal-immunotherapy against multidrug-resistant breast cancer

Abstract

Breast cancer remains a major cause of cancer-related mortality in women, and the development of multidrug resistance (MDR) severely limits the effectiveness of chemotherapy. To address this challenge, a multifunctional liposomal system (RID-LPs) was developed by replacing cholesterol with ginsenoside Rg3 and encapsulating indocyanine green (ICG) and cisplatin (DDP); ICG functions as a photothermal agent capable of generating heat under 808 nm irradiation, while DDP serves as the chemotherapeutic drug, and DSPE-PEG₂₀₀₀ was incorporated to prolong systemic circulation. Ginsenoside Rg3 contributes both structurally and functionally by inhibiting the P-glycoprotein (P-gp) efflux pump, thereby enhancing intracellular drug accumulation; by increasing interaction with glucose transporter 1 (GLUT1), which improves cellular uptake; and by promoting apoptosis through caspase-3 activation. The resulting RID-LPs exhibited stable physicochemical properties and markedly increased internalization in cisplatin-resistant breast cancer (MCF-7/DDP) cells. Upon laser irradiation, ICG-mediated photothermal heating induced pyroptosis and triggered the release of damage-associated molecular patterns (DAMPs), promoting dendritic cell (DC) maturation and enhancing T-cell activation. The combined photothermal effect and cisplatin chemotherapy produced a synergistic antitumor response and effectively reduced MDR. In vivo, RID-LPs demonstrated preferential tumor accumulation, strong tumor growth inhibition, and favorable biosafety. These findings indicate that RID-LPs represent a promising multifunctional nanoplatform capable of decreasing drug efflux, enhancing intracellular delivery, promoting apoptosis, and activating antitumor immune responses for the treatment of drug-resistant breast cancer.