Cancer cell membrane-biomimetic and antioxidant-powered nanoplatform for overcoming multidrug resistance in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is notoriously refractory to chemotherapy because of multidrug resistance (MDR) driven by P-glycoprotein (P-gp) overexpression and oxidative stress in microenvironment (TME). To overcome this, we engineered a triple-action biomimetic nanoplatform (BSA-OPC/siMDR1@CCM) co-encapsulating oligomeric proanthocyanidins (OPC) and MDR1-targeting siRNA (siMDR1) within cancer cell membrane (CCM) cloaked bovine serum albumin (BSA) nanoparticles. The precision-engineered nanoplatform achieved >89 % OPC encapsulation efficiency, complete siMDR1 complexation, pH-responsive drug release (26 % at tumor-mimetic pH 6.5 vs <5 % at systemic pH 7.4), and robust nuclease resistance. In vitro, enhanced cellular uptake and enabled lysosomal escape, achieving 65 % MDR1 knockdown and 85 % ROS suppression to synergistically restore doxorubicin (DOX) sensitivity. In vivo, the nanoplatform showed 7.7-fold greater tumor accumulation versus controls, driving 68 % tumor regression and 100 % 30-day survival in MDR-4T1 models while abolishing metastases. Mechanistic studies confirmed downregulation of P-gp, p53, Ki67, HIF-1α, and ROS without systemic toxicity. This integrated strategy combining targeted delivery, genetic resistance reversal, and microenvironment remodeling, represents a potential strategy against chemorefractory TNBC.