Ultrasound-responsive bacteria-nanocomplex reverses tumor resistance to sensitize chemotherapy/chemodynamic therapy in triple-negative breast cancer

Background Triple-negative breast cancer is in urgent need of precise and effective therapeutic regimens due to drug resistance, which was mainly caused by increased drug efflux based on P-glycoprotein. Therefore, there is an urgent need for precisely regulated therapeutic strategies to reverse tumor drug resistance. Results This study developed an ultrasound-responsive bacterial-nanocomplex △E@PtkDOX-Fe NMs which was able to achieve ideal chemotherapy/chemodynamic therapeutic effect. The experiments showed that △E@PtkDOX-Fe NMs could be ultrasonically modulated to promote reactive oxygen species production, which in turn inhibited the expression of P-glycoprotein in 4T1/ADR cells (P < 0.05) and increased the intracellular accumulation of DOX (P < 0.05), thereby reducing the activity of drug-resistant tumor cells by 63.19% (P < 0.001) and inhibiting the growth of drug-resistant tumors in vivo (P < 0.01). Conclusion In this study, we successfully constructed an ultrasound-responsive bacterial-nanocomplex that can increase the local reactive oxygen species level in tumors and thus reverse tumor drug resistance, which provides a method for accurate and controllable reversal of tumor drug resistance, and establishes a mode of accurate and efficient reversal of tumor drug-resistant sensitizing chemotherapy/chemodynamic therapy. Statement of significance This study developed an ultrasound-responsive bacterial-nanocomplex (△E@PtkDOX-Fe NMs) to overcome P-gp-mediated drug resistance in tumor cells. The complex actively targets tumors via engineered bacterial properties, increasing Fe²⁺ levels in the tumor microenvironment. Meanwhile, △E can upregulates NDH-II levels under ultrasound to elevate H₂O₂ levels, which enhances the Fenton reaction between Fe²⁺ and H₂O₂ to boost ROS generation. These effects trigger DOX release and suppress P-gp expression, sensitizing tumor cells to chemotherapy and improving chemodynamic therapy (CDT) outcomes. This work establishes a spatiotemporally controllable, cascade-amplified combined treatment modality for drug-resistant tumors.