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 (CaCO 3 NPs), which are conjugated to Lactobacillus acidophilus (L. acidophilus , LA) via a polydopamine (PDA) coating. Following tumor accumulation facilitated by bacterial tropism, the CaCO 3 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