cRGD-modified, pH-sensitive liposomes for co-delivery of docetaxel and ABCG2 siRNA enhance therapeutic efficacy in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive malignancy often characterized by chemoresistance, partly due to the overexpression of drug efflux transporters like ABCG2. To address this challenge, this study developed and evaluated a cRGD-modified, pH-sensitive liposomal system for the targeted co-delivery of docetaxel (DTX) and siRNA against ABCG2 (si-ABCG2). The synthesized nanoparticles (DTX/siRNA/cRGD-PLPs) exhibited optimal physicochemical properties, including a mean particle size of approximately 241.7 nm, efficient co-loading of DTX and siRNA, and pH-responsive cargo release, while protecting the siRNA from degradation in serum. Also, DTX/siRNA/cRGD-PLPs maintained homogeneous size distributions over the storage period and induced minimal hemoglobin release, with hemolysis rates remaining below safety threshold. These liposomes demonstrated enhanced, time-dependent uptake into TNBC cell lines HCC1937 and MDA-MB-231. In vitro, the DTX/siRNA/cRGD-PLPs formulation was significantly more effective at inhibiting cell viability, proliferation, migration, and invasion, and at inducing apoptosis, compared to the free drug combinations and other controls. Moreover, the dual-payload co-delivery liposomes (DTX/siRNA/cRGD-PLPs) exerted superior anti-tumor effects relative to single-agent formulations. In an MDA-MB-231 xenograft mouse model, the liposomal treatment was well-tolerated and resulted in marked tumor growth inhibition, which was associated with reduced cell proliferation (Ki67) and increased apoptosis (Caspase-3) within the tumor tissue. This targeted co-delivery system shows significant potential for improving TNBC treatment by synergistically enhancing therapeutic efficacy and overcoming chemoresistance.