Targeted Nanomedicine for Triple-Negative Breast Cancer Closing the Delivery Efficiency Gap

Abstract

Triple-negative breast cancer (TNBC) continues to resist the therapeutic gains achieved in other breast cancer subtypes, and much of that resistance, it turns out, is less about the drugs themselves than about where they end up in the body. Passively targeted nanocarriers were meant to solve this, yet a substantial body of preclinical work now shows that only a median of roughly 0.7% of an intravenously administered nanoparticle dose ever reaches tumor tissue — a figure that helps explain why so much laboratory promise has struggled to survive contact with the clinic. This review draws together evidence on the biological barriers responsible for that shortfall, including mononuclear phagocyte clearance, desmoplastic stroma, elevated interstitial fluid pressure, and an immunosuppressive tumor microenvironment, before turning to the engineering strategies designed to work around them. We examine organic, inorganic, and biomimetic nanocarrier platforms; ligand-based active targeting of biomarkers such as MUC1, CD44, EGFR, and Trop-2; and stimuli-responsive systems that exploit tumor acidosis, redox imbalance, hypoxia, or externally applied triggers to release payload precisely where it is needed. Multimodal strategies — chemo-immunotherapy, phototherapy, radiosensitization — are considered alongside the practical obstacles, GMP scalability, immunogenicity, and preclinical model fidelity chief among them, that continue to slow clinical translation. Rather than treating these as separate literatures, we attempt to place barrier biology, carrier engineering, and translational hurdles into a single, coherent narrative, one that we hope clarifies where the field has made genuine progress and where the delivery efficiency gap remains stubbornly, and instructively, open.