Nano/Micromotors Based on Microbers

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This entry is adapted from the peer-reviewed paper 10.3390/mi14050983

The bio-hybrid micro-nano motors/robots (BMNRs) use a variety of biological carriers, blending the benefits of artificial materials with the unique features of different biological carriers to create tailored functions for specific needs. Compared to cell-based MNRs, microbe-carrier micro-nano robots (MNRs) have very many unique properties. In contrast to most cell-based motors that require active actuation, the most important feature of microbe-based motors is their sensing and self-driving capabilities. Especially, they have good performance in the face of low Reynolds number environments. This is due in large part to the transverse wave that they generate during their movements. This property of converting chemical energy into flagellar-driven mechanical energy allows microbial-based MNRs to be designed with only the manipulation in mind and without the need to provide an additional power source. The most commonly used microbial-based MNRs today include bacterial and algal carriers.

MNRs bio hybrid

1. Nano/Micromotors Based on Bacteria

Bacterial carriers were first used in microfluidic studies ^[1]. Back in 2006, Tung et al. ^[2] immobilized E. coli on the inner surface of a microfluidic chip and relied on the rotation of the bacteria to pump the fluid in the microfluidic channel. Based on the bacteria’s properties, the BMNRs have unusual characteristics. The bacteria are easily modified by engineered plasmids and are highly manipulable, and some bacteria have the good penetrating ability and anti-tumor activity in the face of tumor therapy ^[3]. Bacteria can also respond to a variety of factors in the host environment, including temperature, oxygen, and pH, and thus have a certain degree of chemotaxis ^[4],which allows bacteria to have a very important role in anti-infection and tumor therapy. At the same time, bacteria are inherently immunogenic, which allows them to further stimulate the body’s immunity when delivering drugs to environments with low immunogenicities, such as TME ^[5]. The combination of these factors makes bacterial vector bio-motors primarily relevant in the field of oncology. The sensitivity of bacteria to antibiotics also ensures their biosafety to a certain extent.

Engineered bacteria and bacterial bionic materials are widely used in BMNRs. Rogowski LW et al. ^[6]^[7] have developed a flagellar-propulsion-based nanoparticle, mimicking the flagella of Salmonella typhimurium. Cheng et al. ^[8] designed a composite bacterial robot. This robot is simultaneously sensitive to magnetic, thermal, and hypoxic environments and can improve the reporting of heat and location signals in targeted cancer therapies through internal fluorescent proteins. The perception of magnetism and hypoxia comes from E. coli Nissle 1917 loaded with MNPs, while the reporting of heat and position comes from a thermal-logic circuit loaded within the bacteria. The EcN gene is encoded with the NDH-2 or NDH-2/mCherry gene, which functions to induce reactive oxygen species as a means of anti-tumor therapy. Beyond oncology treatment, bacterial tropism can also be used in oncology diagnosis. Park et al. ^[9] combined attenuated S. typhimurium, which has high athleticism with Cy5.5-coated polystyrene microbeads through the high-affinity interaction between biotin and streptavidin, and performed bacterial detection and localization by arterial luciferase (lux) or green fluorescent protein (GFP) expressed by the bacteria. These bacteria were sensitive to environmental stimuli and their biosafety was ensured because of the attenuated toxicity. However, the low drug-carrying concentration and the limited simulated environment still left several questions about the study.

In biological environments distant from human society, certain rare bacteria deserve our attention. For example, Song et al. ^[10] developed a bacterial robot using magnetotactic cells with powerful motility. The MO-1 bacterium, a type of polar magnetotactic bacteria, can move along magnetic lines of force with the help of its two sturdy flagella. Each flagellum consists of seven filaments enclosed in a specialized sheath and can travel at speeds up to 300 μm/s. The researchers bound the bacteria to polystyrene microbeads using an antigen-antibody reaction, creating a firm bond between them. In experiments, the bacteria swam effortlessly in microfluidic channels, guided by a rotating magnetic field. They also functioned as stirrers and demonstrated potential for detecting and capturing pathogens. Meanwhile, Schürle et al. ^[11] utilized a naturally magnetic bacterium from the Magneto spirillum genus, which contains iron oxide particles. By applying an external rotating magnetic field, they directed the bacterium through the vessel wall near cancer cells. The size of the cell gap in the vessel wall was temporarily adjusted to allow the bacteria to pass through. Notably, rotating magnetic fields offer several advantages over static magnetic fields. The rotating magnetic field is highly propulsive and does not rely on the active movement of bacteria before entering the tumor microenvironment, increasing efficiency. In addition, rotational motion along the vessel wall increases the chances of bacteria entering the vessel wall and reduces off-targeting. Once in the vicinity of the lesion, the bacteria can then be targeted by their chemotaxis to reach the central part of the tumor. However, the team only verified the effect of the magnetic field on bacterial aggregation at the target cells but did not make the bacteria carry the drug, so the clinical efficacy needs to be further investigated.

For tumor therapy, bacterial robots are equally effective. Park et al. ^[12] combined a paclitaxel-loaded liposomal microcargo with tumor-targeting Salmonella typhimurium bacteria. This bacterially driven liposome has a higher mobility compared to regular liposomes and demonstrated a strong tumor-killing ability in an in vitro test based on a breast cancer cell line (4T1), heralding a promising future for a nanomotor based on bacteria in tumor therapy.

Despite their potential as biological vectors, the use of bacteria in this capacity carries several risks. Firstly, due to their pathogenic nature, many bacteria can be rapidly eliminated from the bloodstream by the immune system. Second, achieving effective attachment of bacteria to micro-nanostructures is a challenging task. Lastly, bacteria possess limited propulsive force, which can result in poor targeting and movement of the MNRs. Currently, Listeria, Escherichia, Clostridium, and Salmonella are the most studied bacteria for cancer gene therapy ^[13]^[14]; whereas the specificity of bacterial motors can be controlled by promoters, and specific promoters that are active only when induced by specific factors are most commonly used ^[15].

2. Nano/Micromotors Based on Algae

Algae have also been utilized as carriers for MNRs. Algal cells can convert light energy into mechanical energy through the process of photosynthesis ^[16], and their flagella-driven movement allows them to be used as self-propelling MNRs. Among the different types of algae, Chlamydomonas reinhardtii has been widely studied for its potential in MNR applications.

One of the main advantages of using algae-based MNRs is their ability to be powered by light, which is a non-invasive and renewable energy source. This property has been exploited in the development of light-driven algal micromotors. For instance, Xie et al. ^[1] reported the fabrication of an algal micromotor using Chlamydomonas reinhardtii and demonstrated its ability to transport cargo under light irradiation. The algal micromotor was able to propel itself in response to light and deliver the cargo to a desired location. Another advantage of algae-based MNRs is their biocompatibility and biodegradability ^[1], which makes them a promising option for drug delivery and other biomedical applications. Algae can be easily modified genetically or chemically, and their surface can be functionalized with different targeting molecules or therapeutic agents.

However, there are still several challenges associated with the use of algae-based MNRs. One of the main issues is the limited propulsion force generated by the algae, which can result in inefficient transport of the MNR and its cargo. Additionally, the sensitivity of algae to environmental factors, such as temperature and pH, can affect their viability and functionality. Moreover, the potential immune response elicited by the algal cells needs to be considered when designing algae-based MNRs for biomedical applications. However, not all algae are phototropic, and thus, magnetic nano-beads, which are commonly used in other bio-carrier MNRs, come in handy. Liu et al. ^[17] proposed a biohybrid magnetized microrobot based on Thalassiosira weissflogii frustules to which MNPs are attached by electrostatic adsorption. Algae has a natural porous silica structure, a large surface area, is stable and heat resistant, and is a good carrier for drugs. The diatoms themselves have poor motility, whereas the MNRs designed by this method have high drug-loading capacity, controlled and flexible motion, the ability to switch between two different modes of motion, and the ability to release drugs based on pH sensitivity. By loading doxorubicin, targeted therapy against MCF-7 human breast cancer cells was achieved.

Zhang et al. ^[18] loaded magnetized nanomaterials onto Spirulina by a sol-gel process and loaded it with DOX. The micro-robot not only has an efficient propulsion performance with a maximum speed of 526.2 μm/s under a rotating magnetic field but also has a pH+NIR dual manipulation drug release mechanism with a high drug-loading capacity and a wide range of drug release means. Under the action of a magnetic field, algae can be integrated into clusters. Cai et al. ^[19] covered MNPs with Chlorella and simultaneously loaded DOX. By using magnetic dipolar interactions, the robotic units undergo reversible assembly, reconfiguring into chain-like motors as tiny dimers and trimers. Such aggregates can be rolled and tumbled and can reach speeds of 107.6 μm/s under the application of a magnetic field. The algal motors are highly drug loaded, flexible, simple to manufacture, and pH-sensitive and have also been shown to be tumor-killing in in vitro experiments on Hela cells.

Microbe-based MNRs, including those based on bacteria and algae, offer unique properties and advantages for various applications, such as drug delivery, diagnosis, and environmental sensing. However, there are still several challenges to overcome, such as improving the propulsion force, enhancing targeting capabilities, and ensuring biocompatibility and biosafety. From the existing research on microbial vectors, it is clear that the prevention of immune responses triggered by microbial antigenicity is crucial. Further research and development in this field are needed to optimize microbe-based MNRs and unlock their full potential for a wide range of applications.

References

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Yu Lv

Ruochen Pu

Yining Tao

Xiyu Yang

Haoran Mu

Hongsheng Wang

Wei Sun

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Update Date: 19 May 2023

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1. Nano/Micromotors Based on Bacteria

2. Nano/Micromotors Based on Algae

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