Breast cancer is the leading cause of cancer-related death for women,and multidrug resistance (MDR) is the major obstacle faced by chemotherapy for breast cancer.We have previously synthesized a doxorubicin (DOX) derivative by conjugating DOX with triphenylphosphonium (TPP) to achieve mitochondrial delivery,which induced higher cytotoxicity in drug-resistant breast cancer cells than DOX itself.Due to its amphiphilicity,TPP-DOX is difficult to physically entrap in nanocarriers.Thus,we linked it to hyaluronic acid (HA) by a novel ionic bond utilizing the specific bromide ion of TPP to form supra-molecular self-assembled structures (HA-ionic-TPP-DOX).The product was analyzed uisng 1H-NMR,13C-NMR and mass spectrometry.The HA nanocarriers (HA-ionic-TPP-DOX) were shown to self-assemble into spherical nanoparticles,and sensitive to acidic pH in terms of morphology and drug release.Compared with free DOX,HA-ionic-TPP-DOX produced much greater intracellular DOX accumulation and mitochondrial localization,leading to increased ROS production,slightly decreased mitochondrial membrane potential,increased cytotoxicity in MCF-7/ADR cells and enhanced tumor targeting in vivo.In xenotransplant zebrafish model with the MCF-7/ADR cell line,both TPP-DOX and HA-ionic-TPP-DOX inhibited tumor cell proliferation without inducing significant side effects compared with free DOX.In addition,we observed a better anti-tumor effect of HA-ionic-TPP-DOX on MCF-7/ADR cells in zebrafish than that of TPP-DOX treatment.Furthermore,HA-ionic-DOX-TPP exhibited favorable biocompatibility and anti-tumor effects in MCF-7/ADR tumor-bearing nude mice in comparison with the effects of TPP-DOX and DOX,suggesting the potential of HA-ionic-TPP-DOX for the targeted delivery and controlled release of TPP-DOX,which can lead to the sensitization of resistant breast tumors.