Untethered mobile microrobots has the potential to leverage minimally invasive theranostic functions precisely and efficiently in hard-to-reach, confined, and delicate inner body sites. However, such a complex task requires an integrated design and engineering, where powering, control, environmental sensing, medical functionality and biodegradability need to be considered altogether. The present study reports a hydrogel-based, magnetically powered and controlled, enzymatically degradable microswimmer, which is responsive to the pathological markers in its microenvironment for theranostic cargo delivery and release tasks. We design a double-helical architecture enabling volumetric cargo loading and swimming capabilities under rotational magnetic fields, and 3D printed such optimized 3D microswimmer (length: 20 µm and diameter: 6 µm) using two-photon polymerization from a magnetic precursor suspension comprised from gelatin methacryloyl and biofunctionalized superparamagnetic iron oxide nanoparticles. At normal physiological concentrations, we show that matrix metalloproteinase-2 (MMP-2) enzyme could entirely degrade the microswimmer in 118 h to solubilized non-toxic products. The microswimmer rapidly responds to the pathological concentrations of MMP-2 by swelling, and thereby boosting the release of the embedded cargo molecules. In addition to delivery of the drug type of therapeutic cargo molecules completely to the given microenvironment after full degradation, microswimmer can also release other functional cargos. As an example demonstration, Anti-ErbB 2 antibody-tagged magnetic nanoparticles are released from the fully degraded microswimmers for targeted labeling of SKBR3 breast cancer cells in vitro towards a potential future scenario of medical imaging of remaining cancer tissue sites after a microswimmer-based therapeutic delivery operation.

Complex 3D miniature wireless soft machines for biomedical applications were fabricated with a 3D heterogeneous integration approach.

Biohybrid microrobots, composed of a living organism integrated with an artificial carrier, offer great advantages for the miniaturization of devices with onboard actuation, sensing, and control functionalities and can perform multiple tasks, including manipulation, cargo delivery, and targeting, at nano- and microscales. Over the past decade, various microorganisms and artificial carriers have been integrated to develop unique biohybrid microrobots that can swim or crawl inside the body, in order to overcome the challenges encountered by the current cargo delivery systems. Here, we first focus on the locomotion mechanisms of microorganisms at the microscale, crucial criteria for the selection of biohybrid microrobot components, and the integration of the selected artificial and biological components using various physical and chemical techniques. We then critically review biohybrid microrobots that have been designed and used to perform specific tasks in vivo. Finally, we discuss key challenges, including fabrication efficiency, swarm manipulation, in vivo imaging, and immunogenicity, that should be overcome before biohybrid microrobots transition to clinical use.

Morphology-dependent immunogenicity obliges a compromise on the locomotion-focused design of medical microrobots.