Ginsenoside Rh2- functionalized liposomes enhanced BRD4-PROTAC delivery and antitumor efficacy via improved tumor targeting and ECM remodeling

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. <i>In vitro</i>, Gip significantly improved cellular uptake in 4T1 cells and 3D tumor spheroids <i>via</i> GLUT1-mediated transport, leading to more efficient BRD4 degradation and greater cytotoxicity than lip. <i>In vivo</i>, 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.