Scalable Magnetic Torque Based Actuation Enhances Tumor Infiltration of Bacterial Drug Delivery Vehicles

Bacterial microrobots combining self-propulsion and preferential tumor accumulation have been recognized as promising drug delivery vehicles for targeted cancer therapy. Tumor-targeting bacteria are appealing because of their capacity to autonomously navigate through the body, transport a wide range of payloads, and modulate intratumoral inflammatory responses. Nevertheless, translation of this approach has been hindered by incomplete clinical responses, in part due to insufficient tumor colonization. Developing control strategies to enhance accumulation of bacteria within tumors is essential for facilitating robust colonization while concurrently lowering the required dose of bacteria, thus increasing therapeutic efficacy and safety.<br/><br/>Recently, innately magnetic strains of bacteria acting as steerable therapeutic agents have been manipulated with external magnetic fields. <i>In vivo</i>, strains of magnetotactic bacteria (MTB) carrying payloads have been shown to preferentially proliferate in deoxygenated regions of tumors following magnetic guidance. Magnetic control strategies for these living bacterial microrobots have thus far utilized directing magnetic fields, limited by propulsive forces of the bacterial flagella motor, or poorly scalable magnetic field gradients.<br/><br/>We established a hybrid control strategy that harnesses magnetic torque-driven motion followed by autonomous taxis-based locomotion to enhance the infiltration of <i>Magnetospirillum magneticum</i> AMB-1 as a carrier for covalently-coupled liposomes (MTB-LP). Unlike some forms of magnetic stimulus, uniform rotating magnetic fields (RMF) can be generated at clinically relevant scales for deep sites within the body. We demonstrated the suitability of RMF for simultaneous actuation and inductive detection, which could be exploited for closed-loop operation and real-time monitoring. We also assessed extravasation with computational models and<i> in vitro,</i> and found that the main mechanism driving the enhancement of translocation is increased surface exploration resulting from torque-driven translational motion at the cell interface. In a 3D tumor model, fluorescently labeled MTB-LP achieved stable colonization of the core regions of spheroids, with up to 21-fold higher signal in samples exposed to RMF. Finally, we demonstrated, for the first time to our knowledge, enhanced MTB tumor accumulation under RMF <i>in vivo</i>. Our findings illustrate that the MTB-LP platform combined with an RMF actuation scheme is a versatile biohybrid system that could improve targeting and colonization of therapeutic bacteria in tumors.