From single-pole magnetic tweezers to robotic magnetic-field generation systems, the development of magnetic micromanipulation systems, using electromagnets or permanent magnets, has enabled a multitude of applications for cellular and intracellular measurement and stimulation. Controlled by different configurations of magnetic-field generation systems, magnetic particles have been actuated by an external magnetic field to exert forces/torques and perform mechanical measurements on the cell membrane, cytoplasm, cytoskeleton, nucleus, intracellular motors, etc. The particles have also been controlled to generate aggregations to trigger cell signaling pathways and produce heat to cause cancer cell apoptosis for hyperthermia treatment. Magnetic micromanipulation has become an important tool in the repertoire of toolsets for cell measurement and stimulation and will continue to be used widely for further explorations of cellular/intracellular structures and their functions. Existing review papers in the literature focus on fabrication and position control of magnetic particles/structures (often termed micronanorobots) and the synthesis and functionalization of magnetic particles. Differently, this paper reviews the principles and systems of magnetic micromanipulation specifically for cellular and intracellular measurement and stimulation. Discoveries enabled by magnetic measurement and stimulation of cellular and intracellular structures are also summarized. This paper ends with discussions on future opportunities and challenges of magnetic micromanipulation in the exploration of cellular biophysics, mechanotransduction, and disease therapeutics.

Recent strides in micro- and nanomanufacturing technologies have sparked the development of micro-/nanorobots with enhanced power and functionality. Due to the advantages of on-demand motion control, long lifetime, and great biocompatibility, magnetic propelled micro-/nanorobots have exhibited considerable promise in the fields of drug delivery, biosensing, bioimaging, and environmental remediation. The magnetic fields which provide energy for propulsion can be categorized into rotating and oscillating magnetic fields. In this review, recent developments in oscillating magnetic propelled micro-/nanorobot fabrication techniques (such as electrodeposition, self-assembly, electron beam evaporation, and three-dimensional (3D) direct laser writing) are summarized. The motion mechanism of oscillating magnetic propelled micro-/nanorobots are also discussed, including wagging propulsion, surface walker propulsion, and scallop propulsion. With continuous innovation, micro-/nanorobots can become a promising candidate for future applications in the biomedical field. As a step toward designing and building such micro-/nanorobots, several types of common fabrication techniques are briefly introduced. Then, we focus on three propulsion mechanisms of micro-/nanorobots in oscillation magnetic fields: (1) wagging propulsion; (2) surface walker; and (3) scallop propulsion. Finally, a summary table is provided to compare the abilities of different micro-/nanorobots driven by oscillating magnetic fields.

In cell biology, fluorescent dyes are routinely used for biochemical measurements. The traditional global dye treatment method suffers from low signal-to-noise ratios (SNR), especially when used for detecting a low concentration of ions, and increasing the concentration of fluorescent dyes causes more severe cytotoxicity. Here, we report a robotic technique that controls how a low amount of fluorescent-dye-coated magnetic nanoparticles accurately forms a swarm and increases the fluorescent dye concentration in a local region inside a cell for intracellular measurement. Different from existing magnetic micromanipulation systems that generate large swarms (several microns and above) or that cannot move the generated swarm to an arbitrary position, our system is capable of generating a small swarm (e.g., 1 μm) and accurately positioning the swarm inside a single cell (position control accuracy: 0.76 μm). In experiments, the generated swarm inside the cell showed an SNR 10 times higher than the traditional global dye treatment method. The high-SNR robotic swarm enabled intracellular measurements that had not been possible to achieve with traditional global dye treatment. The robotic swarm technique revealed an apparent pH gradient in a migrating cell and was used to measure the intracellular apparent pH in a single oocyte of living C. elegans. With the position control capability, the swarm was also applied to measure calcium changes at the perinuclear region of a cell before and after mechanical stimulation. The results showed a significant calcium increase after mechanical stimulation, and the calcium increase was regulated by the mechanically sensitive ion channel, PIEZO1.

Structural DNA nanotechnology enables user-prescribed design of DNA nanostructures (DNs) for biological applications, but how DN design determines their bio-distribution and cellular interactions remain poorly understood. One challenge is that current methods for tracking DN fates in situ, including fluorescent-dye labeling, suffer from low sensitivity and dye-induced artifacts. Here we present origamiFISH, a label-free and universal method for single-molecule fluorescence detection of DNA origami nanostructures in cells and tissues. origamiFISH targets pan-DN scaffold sequences with hybridization chain reaction (HCR) probes to achieve thousandfold signal amplification. We identify cell-type and shape-specific spatiotemporal uptake patterns within 1 minute of uptake and at picomolar DN concentrations, 10,000x lower than field standards. We additionally optimized compatibility with immunofluorescence and tissue clearing to visualize DN distribution within tissue cryo/vibratome-sections, slice cultures, and whole-mount organoids. Together, origamiFISH enables faithful mapping of DN interactions across subcellular and tissue barriers for guiding the development of DN-based therapeutics.

Swarms, which stem from collective behaviors among individual elements, are commonly seen in nature. Since two decades ago, scientists have been attempting to understand the principles of natural swarms and leverage them for creating artificial swarms. To date, the underlying physics; techniques for actuation, navigation, and control; fieldgeneration systems; and a research community are now in place. This Review reviews the fundamental principles and applications of micro/ nanorobotic swarms. The generation mechanisms of the emergent collective behaviors among the micro/nanoagents identified over the past two decades are elucidated. The advantages and drawbacks of different techniques, existing control systems, major challenges, and potential prospects of micro/nanorobotic swarms are discussed.