Self-propelled micro/nanorobots have also been used as powerful detoxification tools with high cleaning capability. Similar to biosensing, detoxification strategies rely on self-propelled micro/nanorobots that rapidly capture and remove the toxin to render the environment nontoxic. Efficient motion would facilitate the collision and binding of toxins to the motors, which are coated with desired functional materials. For example, nanomotors have been combined with cell-derived natural materials—capable of mimicking the natural properties of their source cells—toward novel nanoscale biodetoxification devices. Among different cell derivatives, red blood cells (RBCs) have shown excellent capability to function as toxin-absorbing nanosponges to neutralize and remove dangerous “pore-forming toxins” (PFTs) from the bloodstream (
Fig. 5A) (
81). Motivated by the biological properties of RBCs, several different types of cell-mimicking micromotors have been developed for detoxification. Wu
et al. (
82) presented a cell-mimicking, water-powered micromotor based on RBC membrane–coated magnesium microparticles, which were able to effectively absorb and neutralize α-toxin in biological fluids (
Fig. 5B). Another detoxification strategy explored the combination of RBC membranes with ultrasound-propelled nanomotors as a biomimetic platform to effectively absorb and neutralize PFTs (
41). Another microrobot-based detoxification approach was based on the use of a self-propelled three-dimensional (3D)–printed microfish containing polydiacetylene nanoparticles (
Fig. 5C, top), which served to attract, capture, and neutralize toxins via binding interactions (
83). Self-propelled 3D microfishes incubated in the toxin solution showed higher fluorescence intensities (
Fig. 5C, bottom) compared with static microfishes, highlighting the importance of active motion for enhancing the detoxification processes.
Conclusions, gaps, and outlook
Over the past decade, micro/nanorobotics has emerged as a novel and versatile platform to integrate the advantages of nanotechnologies and robotic sciences. A diverse set of design principles and propulsion mechanisms have thus led to the development of highly capable and specialized micro/nanorobots. These micro/nanorobots have unique and multivalent functionalities, including fast motion in complex biological media, large cargo-towing force for directional and long-distance transport, easy surface functionalization for precise capture and isolation of target individuals, and excellent biocompatibility for in vivo operation. These attractive functionalities and capabilities of micro/nanorobots have facilitated biomedical applications, ranging from targeted delivery of payloads and precise surgery on a cellular level to ultrasensitive detection of biological molecules and rapid removal of toxic compounds. These developments have advanced the micro/nanorobots from chemistry laboratories and test tubes to whole living systems. Such in vivo studies serve as an important step forward toward clinical translation of the micro/nanorobots.
The ability of micro/nanorobots to address health care issues is just in its infancy. Overcoming knowledge gaps in nanorobotics could have a profound impact on different medical domains. Tremendous efforts and innovations are required for realizing the full potential of these tiny robots for performing complex operations within body locations that were previously inaccessible. Future micro/nanorobots must mimic the natural intelligence of their biological counterparts (e.g., microorganisms and molecular machines) with high mobility, deformable structure, adaptable and sustainable operation, precise control, group behavior with swarm intelligence, sophisticated functions, and even self-evolving and self-replicating capabilities.
A significant challenge is to identify new energy sources for prolonged, biocompatible, and autonomous in vivo operation. Although different chemical fuels and external stimuli have been explored for nanoscale locomotion in aqueous media (
8), new alternative fuels and propulsion mechanisms are necessary for safe and sustainable operation in the human body. Most of the catalytic micromotors rely on hydrogen peroxide fuel and hence can only be used in vitro. Micromotors powered by active material propellants (e.g., Mg, Zn, Al, and CaCO
3) have relatively short lifetimes because of rapid consumption of their propellant during their propulsion. Recent efforts have indicated that enzyme-functionalized nanomotors could be powered by bodily fluid constituents, such as blood glucose or urea (
84–
86). The power and stability of these enzyme-based motors require further improvements for practical implementation. Magnetic and acoustic nanomotors can provide fuel-free and on-demand speed regulation, which is highly suitable for nanoscale surgery but may hinder autonomous therapeutic interventions.
Moving nanorobots from test tubes to living organisms would require significant future efforts. The powerful performance of micro/nanorobots has already been demonstrated in viscous biological fluids such as gastric fluid or whole blood (
34,
35,
57,
87,
88). Operating these tiny devices in human tissues and organs that impose larger barriers to motion requires careful examination. Magnetically powered microswimmers have been successfully actuated in the peritoneal cavity of a mouse using a weak rotating magnetic field of 9 mT (
36). Magneto-aerotactic bacteria were able to migrate into tumor hypoxic regions under a focalized directional magnetic field of only 15 G (
37). Ultrasound-powered micromotors with powerful “ballistic” capabilities have enabled deep tissue penetration (
65). Powering nanorobot within tissues and organs could greatly benefit from their small size. Such “small is better” philosophy has already been verified using nanoscale magnetic propellers, which display a significant advantage for propulsion in viscoelastic hyaluronan gels because they are of the same size range as the openings in the gel’s mesh, compared with the impeded motion of larger propellers (
89). These results demonstrate that nanorobots are highly promising for achieving efficient motion in tissues enabled by the nanoscale size and optimized design. The miniaturization advantages of smaller nanorobots have also been realized for overcoming cellular barriers and internalizing into cells (
55).
Designing robots to perform tasks at the nanoscale is essentially a materials science or surface science problem because the operation and intelligence of tiny robots rely primarily on their materials and surface properties. Biomedical nanorobots are designed for environments involving unanticipated biological events, changing physiological conditions, and soft tissues. Therefore, diverse smart materials, such as biological materials, responsive materials, or soft materials, are highly desired to provide the necessary actuation and multifunctionality while avoiding irreversible robotic malfunctions in complex physiologically relevant body systems. Recent report has shown that the macrophage uptake of rotating magnetic microrobots could be avoided by adjusting the rotational trap stiffness (
90). Alternatively, coupling synthetic nanomachines with natural biological materials can minimize undesired immune evasion and biofouling effects experienced in complex biological fluids, leading to enhanced mobility and lifetime in these media (
82). Responsive materials are highly desired for designing configurable nanorobots for adaptive operation under rapidly changing conditions. Nanorobots are also desired to be soft and deformable to ensure maneuverability and mechanical compliance to human body and tissues (
91,
92). Eventually, they should be made of transient biodegradable materials that disappear upon completing their tasks (
93). New fabrication and synthesis approaches, such as 3D nanoprinting, should be explored for large-scale, high-quality, and cost-efficient fabrication of biomedical nanorobots. Advancing nanorobots into the next level will thus be accomplished with new smart materials and cutting-edge fabrication techniques.
Biomedical nanorobots are expected to cooperate, with thousands of units moving independently and coordinately to target the disease site. The coordinated action of multiple nanorobots could be used for performing tasks (e.g., effective delivery of large therapeutic payloads or large-scale detoxification processes) that are not possible using a single robot. Although individual navigation and collective behavior of nanorobots have been explored, mimicking the natural intelligence group communication and synchronized coordination, from one to many, is a challenging issue. Advancing the swarm intelligence of nanorobots toward group motion planning and machine learning at the nanoscale is highly important for enhancing their precision treatment capability. Fundamental understanding of “active matter” and related quantitative control theory can guide the realization of such swarming behavior in dynamically changing environments. High-resolution simultaneous localization and mapping of nanorobots in the human body are experimentally difficult using conventional optical microscopy techniques. Future biomedical operation of nanorobots will require their coupling with modern imaging systems and feedback control systems for arbitrary 4D navigation of many-nanorobot systems.
Looking to the future, the development and application of micro/nanorobots in medicine is expected to become a vigorous research area. To realize the full potential of the micro/nanorobots in the medical field, nanorobotic scientists should work more closely with medical researchers for thorough investigations of the behavior and functionality of the robots, including studies on their biocompatibility, retention, toxicity, biodistribution, and therapeutic efficacy. Considering the promising results achieved recently in GI delivery and ophthalmic therapies, we strongly encourage nanorobotic scientists to look into the demands and needs of the medical community to design problem-oriented medical device for specific diagnostic or therapeutic functions. Addressing these specific needs will lead to accelerated translation of micro/nanorobots research into practical clinical use. We envision that with close collaboration between the nanorobotic and medical communities, these challenges can be gradually addressed, eventually expanding the horizon of micro/nanorobots in medicine.
