Tumor microenvironment-regulated drug delivery system combined with sonodynamic therapy for the synergistic treatment of breast cancer.

Co-loading of sonosensitizers and chemotherapeutic drugs into nanocarriers can improve the biocompatibilities, stabilities, and targeting of drugs and reduce the adverse reactions of drugs, providing a robust platform to orchestrate the synergistic interplay between chemotherapy and sonodynamic therapy (SDT) in cancer treatment. In this regard, biodegradable manganese dioxide (MnO) has attracted widespread attention because of its unique properties in the tumor microenvironment (TME). Accordingly, herein, MnO nanoshells with hollow mesoporous structures (H-MnO) were etched to co-load hematoporphyrin monomethyl ether (HMME) and doxorubicin (DOX), and DOX/HMME-HMnO@bovine serum albumin (BSA) obtained after simple BSA modification of DOX/HMME-HMnO exhibited excellent hydrophilicity and dispersibility. H-MnO rapidly degraded in the weakly acidic TME, releasing loaded HMME and DOX, and catalysed the decomposition of HO abundantly present in TME, producing oxygen (O) , significantly increasing O concentration and downregulating the hypoxia-inducible factor 1α (HIF-1α). After irradiation of the tumor area with low-frequency ultrasound, the drug delivery efficiency of DOX/HMME-HMnO@BSA substantially increased, and the excited HMME generated a large amount of reactive oxygen species (ROS), which caused irreversible damage to tumor cells. Moreover, the cell death rate exceeded 60% after synergistic SDT-chemotherapy. Therefore, the pH-responsive nanoshells designed in this study can realize drug accumulation in tumor regions by responding to TME and augment SDT-chemotherapy potency for breast cancer treatment by improving hypoxia in tumors. Thus, this study provides theoretical support for the development of multifunctional nanocarriers and scientific evidence for further exploration of safer and more efficient breast cancer treatments.