For drug delivery in cancer therapy, various stimuli-responsive hydrogel-based micro-devices have been studied with great interest. Here, we present a new concept for a hybrid actuated soft microrobot targeted drug delivery. The proposed soft microrobot consists of a hydrogel bilayer structure of 2-hydroxyethyl methacrylate (PHEMA) and poly (ethylene glycol) acrylate (PEGDA) with iron (II, III) oxide particles (Fe 3 O 4 ). The PHEMA layer as a pH-responsive gel is used for a trapping and unfolding motion of the soft microrobot in pH-varying solution, and the PEGDA-with-Fe 3 O 4 layer is employed for the locomotion of the soft microrobot in the magnetic field. The bilayer soft microrobot was fabricated by a conventional photolithography procedure and its characteristics were analyzed and presented. To evaluate the trapping performance and the motility of the soft microrobot, test solutions with different pH values and an electromagnetic actuation (EMA) system were used. First, the soft microrobot showed its full trapping motion at about pH 9.58 and its unfolding motion at about pH 2.6. Second, the soft microrobot showed a moving velocity of about 600 μm s −1 through the generated magnetic field of the EMA system. Finally, we fabricated the real anti-cancer drug microbeads (PCL-DTX) and executed the cytotoxicity test using the mammary carcinoma cells (4T1). The viability of the 4T1 cells treated with the proposed microrobot and the PCL-DTX microbeads decreased to 70.25±1.52%. The result demonstrated that the soft microrobot can be moved to a target position by the EMA system and can release a small amount of beads by the pH variation and the robot exhibited no toxicity to the cells. In the future, we expect that the proposed soft microrobot can be applied to a new tumor-therapeutic tool that can move to a target tumor and release anti-tumor drugs.

We propose a bacteria-based microrobot (bacteriobot) based on a new fusion paradigm for theranostic activities against solid tumors. We develop a bacteriobot using the strong attachment of bacteria to Cy5.5-coated polystyrene microbeads due to the high-affinity interaction between biotin and streptavidin. The chemotactic responses of the bacteria and the bacteriobots to the concentration gradients of lysates or spheroids of solid tumors can be detected as the migration of the bacteria and/or the bacteriobots out of the central region toward the side regions in a chemotactic microfluidic chamber. The bacteriobots showed higher migration velocity toward tumor cell lysates or spheroids than toward normal cells. In addition, when only the bacteriobots were injected to the CT-26 tumor mouse model, Cy5.5 signal was detected from the tumor site of the mouse model. In-vitro and in-vivo tests verified that the bacteriobots had chemotactic motility and tumor targeting ability. The new microrobot paradigm in which bacteria act as microactuators and microsensors to deliver microstructures to tumors can be considered a new theranostic methodology for targeting and treating solid tumors.

We developed a novel method to fabricate a crab-like microrobot that can actuate for a long period in a physiological condition. The microrobot backbone was built with a biocompatible and elastic material-polydimethylsiloxane (PDMS)-by using a specially designed 3D molding aligner, and consisted of three strips of PDMS "legs" connected across a "body." Cardiomyocytes were then plated on the grooved top surface of the backbone, resulting in a high concentration of pulsating cells. These key techniques enabled the microrobot to walk continuously for over ten days. The performance of our crab-like microrobot was measured at an average velocity of 100 microm s(-1), and the estimated total distance it travelled was 50 m over a one-week period. Thus, we have demonstrated for the first time a walking robot that exhibited reliable and long-term actuation performances.

Using macrophage recruitment in tumors, we develop active, transportable, cancer theragnostic macrophage-based microrobots as vector to deliver therapeutic agents to tumor regions. The macrophage-based microrobots contain docetaxel (DTX)-loaded poly-lactic-co-glycolic-acid (PLGA) nanoparticles (NPs) for chemotherapy and Fe3O4 magnetic NPs (MNPs) for active targeting using an electromagnetic actuation (EMA) system. And, the macrophage-based microrobots are synthesized through the phagocytosis of the drug NPs and MNPs in the macrophages. The anticancer effects of the microrobots on tumor cell lines (CT-26 and 4T1) are evaluated in vitro by cytotoxic assay. In addition, the active tumor targeting by the EMA system and macrophage recruitment, and the chemotherapeutic effect of the microrobots are evaluated using three-dimensional (3D) tumor spheroids. The microrobots exhibited clear cytotoxicity toward tumor cells, with a low survivability rate (<50%). The 3D tumor spheroid assay showed that the microrobots demonstrated hybrid actuation through active tumor targeting by the EMA system and infiltration into the tumor spheroid by macrophage recruitment, resulting in tumor cell death caused by the delivered antitumor drug. Thus, the active, transportable, macrophage-based theragnostic microrobots can be considered to be biocompatible vectors for cancer therapy.

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Nanorobots are safe and exhibit powerful functionalities, including delivery, therapy, and diagnosis. Therefore, they are in high demand for the development of new cancer therapies. Although many studies have contributed to the progressive development of the nanorobot system for anticancer drug delivery, these systems still face some critical limitations, such as potentially toxic materials in the nanorobots, unreasonable sizes for passive targeting, and the lack of several essential functions of the nanorobot for anticancer drug delivery including sensing, active targeting, controlling drug release, and sufficient drug loading capacity. Here, we developed a multifunctional nanorobot system capable of precise magnetic control, sufficient drug loading for chemotherapy, light-triggered controlled drug release, light absorption for photothermal therapy, enhanced magnetic resonance imaging, and tumor sensing. The developed nanorobot system exhibits an in vitro synergetic antitumor effect of photothermal therapy and chemotherapy and outstanding tumor-targeting efficiency in both in vitro and in vivo environments. The results of this study encourage further explorations of an efficient active drug delivery system for cancer treatment and the development of nanorobot systems for other biomedical applications.

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