Dual-cargo polymeric micelles with tumor-cell/stroma dual-targeting for synergistic eradication of drug-resistant breast cancer.

Therapeutic resistance in breast cancer, driven by tumor-intrinsic adaptive mechanisms and microenvironmental survival cues, remains a critical barrier to curative treatment. To address this dual challenge, we developed a redox-responsive polymeric micelle system (TPSP) functionalized with telmisartan for simultaneous targeting of angiotensin II type 1 receptor-overexpressing tumor cells and cancer-associated fibroblasts (CAFs). This platform co-encapsulates doxorubicin (DOX), a classic topoisomerase IIα (Topo IIα) poison, and aconitine linoleate (L29), a novel catalytic Topo IIα inhibitor with a distinct mechanism of action compared with conventional agents. The TPSP micelles exhibit dual therapeutic synergism: (1) L29 disrupts DNA replication through G1/S cell cycle arrest via Topo IIα catalytic inhibition, complementing DOX's DNA double-strand break induction to counter acquired resistance, and (2) telmisartan-mediated CAF depletion disrupts stromal-mediated drug resistance by eliminating metabolic symbiosis and biomechanical barriers. In vivo evaluations across resistant breast cancer models revealed superior tumor growth inhibition (>72%) with CAF ablation. This combinatorial nanomedicine strategy pioneers a paradigm shift in overcoming multidrug resistance by concurrently targeting tumor plasticity and microenvironmental protection, providing a clinically translatable blueprint for treatment-refractory malignancies.