Magnetic torque–driven living microrobots for increased tumor infiltration

Abstract

Biohybrid bacteria–based microrobots are increasingly recognized as promising externally controllable vehicles for targeted cancer therapy. Magnetic fields in particular have been used as a safe means to transfer energy and direct their motion. Thus far, the magnetic control strategies used in this context rely on poorly scalable magnetic field gradients, require active position feedback, or are ill-suited to diffuse distributions within the body. Here, we present a magnetic torque–driven control scheme for enhanced transport through biological barriers that complements the innate taxis toward tumor cores exhibited by a range of bacteria, shown for Magnetospirillum magneticum as a magnetically responsive model organism. This hybrid control strategy is readily scalable, independent of position feedback, and applicable to bacterial microrobots dispersed by the circulatory system. We observed a fourfold increase in translocation of magnetically responsive bacteria across a model of the vascular endothelium and found that the primary mechanism driving increased transport is torque-driven surface exploration at the cell interface. Using spheroids as a three-dimensional tumor model, fluorescently labeled bacteria colonized their core regions with up to 21-fold higher signal in samples exposed to rotating magnetic fields. In addition to enhanced transport, we demonstrated that our control scheme offers further advantages, including the possibility for closed-loop optimization based on inductive detection, as well as spatially selective actuation to reduce off-target effects. Last, after systemic intravenous injection in mice, we showed significantly increased bacterial tumor accumulation, supporting the feasibility of deploying this control scheme clinically for magnetically responsive biohybrid microrobots.

Magnetospirillum magneticum triggers apoptotic pathways in human breast cancer cells

“…With a demonstrated ability to successfully impact the metabolism of breast cancer cells in vitro, AMB-1 were shown to affect the proliferation of MDA-MB-231 cells and trigger apoptosis. Previous studies highlighted the ability of magnetotactic bacteria to in ltrate across biological barriers in vitro and in vivo, and to proliferate in solid tumors [15]. With this work we demonstrate the capability of AMB-1 to induce apoptosis in cancer cells possibly through iron competition in the tumor microenvironment [22].…”

“…These microorganisms employ their migratory and chemotactic abilities to overcome tissue barriers normally inaccessible for conventional drug-based therapies. To date, a broad number of bacterial classes such as Clostridium, Salmonella, Listeria, Bi dobacterium, Lactobacilli, Escherichia and Magnetospirillum are being increasingly studied for this purpose, with some already advancing to clinical trials [14][15][16].…”

“…Additionally, these magnetosomes allow the MTB to be detected and guided by externally applied magnetic elds [20]. In bacterial cancer therapy, their native localization in hypoxic regions of solid tumors can be magnetically increased [15,21], and their enhanced requirement for iron might cause inducible iron competition and depletion within the tumor environment, possibly resulting in a decreased viability of cancer cells [22].…”

Printing on Particles: Combining Two‐Photon Nanolithography and Capillary Assembly to Fabricate Multimaterial Microstructures

“…The actuation of the magnetic structures was achieved using a small‐scale arbitrary magnetic field generator consisting of eight electromagnets arranged in a single hemisphere, which was used to apply RMF (MFG‐100‐i, MagnebotiX, Zürich, Switzerland). [ 50 ] The system was integrated with an inverted microscope (Nikon Eclipse Ti2). Samples were positioned between the objective lens and the hemisphere of the electromagnets.…”

Acoustic trapping and navigation of microrobots in the mouse brain vasculature

“…Magnetic and acoustic external fields have been shown to be suitable for guiding microrobots within living tissue (29)(30)(31)(32)(33)(34)(35)(36)(37). Such manipulations have been seen for organs with low/no flow such as the stomach (38), urinary bladder (39,40), liver portal vein (41), ear vasculature (42), intestine (43), lung tissue (44), cremaster muscle (45), knee cartilage (46), and cutaneous and subcutaneous vasculature (47,48). Within the brain, only magnetic microrobots have been explored to date, and limited manipulation in situ mouse models was demonstrated with them (30).…”