Bacteria-powered LA@CaDGP biomotor: a multi-modal weapon integrating calcium overload, chemotherapy, and starvation for breast cancer therapy

Abstract Chemotherapy remains a cornerstone in breast cancer treatment, but poor drug targeting compromises its efficacy and exacerbates side effects. To optimize drug delivery, we developed a novel bacteria-propelled biomotor system, designated as LA@CaDGP, to enhance the tumor-specific drug delivery. The biomotor was engineered to load doxorubicin (DOX) and glucose oxidase (GOD) within mesoporous calcium carbonate nanoparticles (CaCO3 NPs), which are conjugated to Lactobacillus acidophilus (L. acidophilus, LA) via a polydopamine (PDA) coating. Following tumor accumulation facilitated by bacterial tropism, the CaCO3 component undergoes dissolution, releasing calcium ions that induce mitochondrial dysfunction and thereby potentiate the chemotherapeutic efficacy of DOX. Concurrently, the GOD-mediated glucose depletion effect synergistically enhances antitumor activity through metabolic intervention. In a mouse orthotopic breast cancer model, the LA@CaDGP group showed a tenfold higher DOX concentration in tumor tissues compared to conventional free DOX administration, while the DOX concentration in heart tissues was 24 times lower. Mice in the LA@CaDGP group achieved a median survival time of 50 days. Collectively, these findings collectively demonstrate that the LA@CaDGP biomotor constitutes a promising therapeutic platform for breast cancer, integrating multiple synergistic mechanisms: calcium overload-mediated cytotoxicity, conventional chemotherapy, and metabolic starvation therapy. Graphical Abstract In this study, an oral self-propelled biomotor called LA@CaDGP was designed to simultaneously deliver the chemotherapeutic drug doxorubicin and glucose oxidase for a combination of chemotherapy and starvation therapy to fight breast cancer. These biomotors actively gathered in the tumor and achieved improved anti-tumor effects by directly killing tumor cells, depleting cellular nutrients, and boosting calcium overload.