Ginsenoside Rh2- functionalized liposomes enhanced BRD4-PROTAC delivery and antitumor efficacy via improved tumor...

PROTAC technology leverages the ubiquitin-proteasome system to selectively degrade target proteins, presenting a novel strategy for anticancer therapy. ARV825, a BRD4-targeting PROTAC, exerts potent antitumor effects by degrading BRD4, thereby suppressing Bcl-2 and PD-L1 expression, inducing apoptosis, and enhancing T cell-mediated immunity. However, its clinical translation is hindered by poor solubility, low membrane permeability, and off-target effects. While conventional liposomes (lip) improved ARV825 delivery, their efficacy remained limited by insufficient tumor targeting and collagen-rich extracellular matrix (ECM) barriers that restricted T cell infiltration. To address these challenges, ginsenoside Rh2 (GRh2)-functioned liposomes (Gip) were developed by replacing cholesterol with GRh2. Gip exhibited high drug encapsulation efficiency and superior stability. In vitro, Gip significantly improved cellular uptake in 4T1 cells and 3D tumor spheroids via GLUT1-mediated transport, leading to more efficient BRD4 degradation and greater cytotoxicity than lip. In vivo, Gip demonstrated superior tumor accumulation in subcutaneous and lung metastasis models, owing to its active targeting capability. Crucially, GRh2-mediated collagen degradation synergized with ARV825-induced PD-L1 suppression to enhance T cell infiltration. As a result, ARV@Gip exhibited superior antitumor efficacy through dual mechanisms, including enhanced apoptosis and immune activation, outperforming ARV@lip in both tumor models. Collectively, this GRh2-functionalized liposomal platform overcomes key pharmacological barriers by integrating enhanced tumor targeting, ECM modulation, and dual pro-apoptotic/immunostimulatory effects, offering a promising therapeutic strategy for breast cancer.