Untethered mobile microrobots have 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 a 3D-printed optimized 3D microswimmer (length = 20 μm and diameter = 6 μm) using two-photon polymerization from a magnetic precursor suspension composed 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 nontoxic 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, microswimmers 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 toward a potential future scenario of medical imaging of remaining cancer tissue sites after a microswimmer-based therapeutic delivery operation.

Advances in design and fabrication of functional micro/nanomaterials have sparked growing interest in creating new mobile microswimmers for various healthcare applications, including local drug and other cargo ( e. g., gene, stem cell, and imaging agent) delivery. Such microswimmer-based cargo delivery is typically passive by diffusion of the cargo material from the swimmer body; however, controlled active release of the cargo material is essential for on-demand, precise, and effective delivery. Here, we propose a magnetically powered, double-helical microswimmer of 6 μm diameter and 20 μm length that can on-demand actively release a chemotherapeutic drug, doxorubicin, using an external light stimulus. We fabricate the microswimmers by two-photon-based 3D printing of a natural polymer derivative of chitosan in the form of a magnetic polymer nanocomposite. Amino groups presented on the microswimmers are modified with doxorubicin by means of a photocleavable linker. Chitosan imparts the microswimmers with biocompatibility and biodegradability for use in a biological setting. Controlled steerability of the microswimmers is shown under a 10 mT rotating magnetic field. With light induction at 365 nm wavelength and 3.4 × 10 W/cm intensity, 60% of doxorubicin is released from the microswimmers within 5 min. Drug release is ceased by controlled patterns of light induction, so as to adjust the desired release doses in the temporal domain. Under physiologically relevant conditions, substantial degradation of the microswimmers is shown in 204 h to nontoxic degradation products. This study presents the combination of light-triggered drug delivery with magnetically powered microswimmer mobility. This approach could be extended to similar systems where multiple control schemes are needed for on-demand medical tasks with high precision and efficiency.

Bacteria-propelled biohybrid microswimmers have recently shown to be able to actively transport and deliver cargos encapsulated into their synthetic constructs to specific regions locally. However, usage of synthetic materials as cargo carriers can result in inferior performance in load-carrying efficiency, biocompatibility, and biodegradability, impeding clinical translation of biohybrid microswimmers. Here, we report construction and external guidance of bacteria-driven microswimmers using red blood cells (RBCs; erythrocytes) as autologous cargo carriers for active and guided drug delivery. Multifunctional biohybrid microswimmers were fabricated by attachment of RBCs [loaded with anticancer doxorubicin drug molecules and superparamagnetic iron oxide nanoparticles (SPIONs)] to bioengineered motile bacteria, Escherichia coli MG1655, via biotin-avidin-biotin binding complex. Autonomous and on-board propulsion of biohybrid microswimmers was provided by bacteria, and their external magnetic guidance was enabled by SPIONs loaded into the RBCs. Furthermore, bacteria-driven RBC microswimmers displayed preserved deformability and attachment stability even after squeezing in microchannels smaller than their sizes, as in the case of bare RBCs. In addition, an on-demand light-activated hyperthermia termination switch was engineered for RBC microswimmers to control bacteria population after operations. RBCs, as biological and autologous cargo carriers in the biohybrid microswimmers, offer notable advantages in stability, deformability, biocompatibility, and biodegradability over synthetic cargo-carrier materials. The biohybrid microswimmer design presented here transforms RBCs from passive cargo carriers into active and guidable cargo carriers toward targeted drug and other cargo delivery applications in medicine.

High-performance, multifunctional bacteria-driven microswimmers are introduced using an optimized design and fabrication method for targeted drug delivery applications. These microswimmers are made of mostly single Escherichia coli bacterium attached to the surface of drug-loaded polyelectrolyte multilayer (PEM) microparticles with embedded magnetic nanoparticles. The PEM drug carriers are 1 μm in diameter and are intentionally fabricated with a more viscoelastic material than the particles previously studied in the literature. The resulting stochastic microswimmers are able to swim at mean speeds of up to 22.5 μm/s. They can be guided and targeted to specific cells, because they exhibit biased and directional motion under a chemoattractant gradient and a magnetic field, respectively. Moreover, we demonstrate the microswimmers delivering doxorubicin anticancer drug molecules, encapsulated in the polyelectrolyte multilayers, to 4T1 breast cancer cells under magnetic guidance in vitro. The results reveal the feasibility of using these active multifunctional bacteria-driven microswimmers to perform targeted drug delivery with significantly enhanced drug transfer, when compared with the passive PEM microparticles.

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Untethered synthetic microrobots have significant potential to revolutionize minimally invasive medical interventions in the future. However, their relatively slow speed and low controllability near surfaces typically are some of the barriers standing in the way of their medical applications. Here, we introduce acoustically powered microrobots with a fast, unidirectional surface-slipping locomotion on both flat and curved surfaces. The proposed threedimensionally printed, bullet-shaped microrobot contains a spherical air bubble trapped inside its internal body cavity, where the bubble is resonated using acoustic waves. The net fluidic flow due to the bubble oscillation orients the microrobot's axisymmetric axis perpendicular to the wall and then propels it laterally at very high speeds (up to 90 body lengths per second with a body length of 25 μm) while inducing an attractive force toward the wall. To achieve unidirectional locomotion, a small fin is added to the microrobot's cylindrical body surface, which biases the propulsion direction. For motion direction control, the microrobots are coated anisotropically with a soft magnetic nanofilm layer, allowing steering under a uniform magnetic field. Finally, surface locomotion capability of the microrobots is demonstrated inside a threedimensional circular cross-sectional microchannel under acoustic actuation. Overall, the combination of acoustic powering and magnetic steering can be effectively utilized to actuate and navigate these microrobots in confined and hard-to-reach body location areas in a minimally invasive fashion. microrobots | acoustic actuation | magnetic control | microswimmers | bubble oscillation U ntethered synthetic microrobots have been recently investigated for their potential applications in targeted drug delivery, detoxification, and noninvasive surgeries (1-4). The existing microswimmers are powered by different external energy sources, such as light (5-7), electrical (8,9), magnetic (10, 11), and acoustic (12, 13) fields, or fueled by chemicals in the environment (14, 15). Among these actuation schemes, magnetic and acoustic field-based powering methods are the most prevalent in the biomedical context thanks to their deep-tissue penetration and high-energy-density capabilities. While the acoustic waves can deliver strong propulsion forces (16), the magnetic field can provide controlled steering of the microswimmers (17, 18). For example, acoustically excited bubbles can generate high streaming forces (16,19), and when employed in the robot's body they can act as an engine for the propulsion (12,20).Up to now, a few studies have used two-dimensional (2D) microfabrication (20, 21) and ultraviolet light-based polymerization techniques (12,22) to fabricate around 100-to 300-μm microrobots with cylindrical or conical cavities for bubble entrapment. As the bubble diameter scales down to the 10-to 30-μm range, the cylindrical cavity geometry would require advanced hydrophobic treatment to hold a microbubble stable due to the increased surface tens...

Recent advances in the versatility and sophistication of design, fabrication, and control methods of mobile microrobots could have a transforming impact on future healthcare technologies. Self-propelled or remotely actuated, synthetic, or biohybrid microrobots can navigate to difficult-to-reach regions in the human body to deliver therapeutics for microscopically localized medical interventions. Here, recent progress in the design of microrobotic systems concerning therapeutic delivery of drugs, cells, and genetic materials is reported. This perspective prioritizes the design aspects of microrobots for medical cargo loading, navigation in biologically relevant environments, and controlled cargo release. In the final section, future prospects and a discussion on the critical shortcomings for the benchside-to-bedside translation of medical microrobots are provided.

Nature presents intriguing biological swimmers with innate energy harvesting abilities from their local environments. Use of natural swimmers as cargo delivery agents presents an alternative strategy to transport therapeutics inside the body to locations otherwise difficult to access by traditional delivery strategies. Herein, a biocompatible biohybrid microswimmer powered by a unicellular freshwater green microalga, Chlamydomonas reinhardtii, is reported. Polyelectrolyte‐functionalized magnetic spherical cargoes (1 µm in diameter) are attached to surface of the microalgae via noncovalent interactions without the requirement for any chemical reaction. The 3D swimming motility of the constructed biohybrid algal microswimmers is characterized in the presence and absence of a uniform magnetic fields. In addition, motility of both microalgae and biohybrid algal microswimmers is investigated in various physiologically relevant conditions, including cell culture medium, human tubal fluid, plasma, and blood. Furthermore, it is demonstrated that the algal microswimmers are cytocompatible when co‐cultured with healthy and cancerous cells. Finally, fluorescent isothiocyanate‐dextran (a water‐soluble polysaccharide) molecules are effectively delivered to mammalian cells using the biohybrid algal microswimmers as a proof‐of‐concept active cargo delivery demonstration. The microswimmer design described here presents a new class of biohybrid microswimmers with greater biocompatibility and motility for targeted delivery applications in medicine.