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Micro/Nanomotors on the Way to Intelligent Cancer Diagnosis, Delivery and Therapy

Jiajia Wang , Huiying Wu , Renfeng Dong , Yuepeng Cai

Progress in Chemistry ›› 2021, Vol. 33 ›› Issue (5) : 883 -894.

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Progress in Chemistry ›› 2021, Vol. 33 ›› Issue (5) : 883-894 DOI: 10.7536/PC200660
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Micro/Nanomotors on the Way to Intelligent Cancer Diagnosis, Delivery and Therapy
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Abstract

Cancers seriously threaten human health due to their relatively high mortality. Early diagnosis and treatment play key roles in improving the cancers cure rate and saving people’s lives. With the development of science and nanotechnology, the advent of micro/nanomotors with self-propelled capabilities has enabled exciting opportunities for the diagnosis and therapy of cancers. The micro/nanomotors can effectively convert diverse energy sources(light, ultrasound, magnetic, electrical, heat, etc.) into their own driving forces, and show encouraging potential for performing various complex and precise tasks in the micrometer or nanometer space. Compared with nanomaterials with passive Brownian motion, micro/nanomotors with active propulsion capabilities endow more flexibility in intelligent cancer diagnosis and treatment. With the development of fabrication strategies, various shapes of micro/nanomotors that can be driven in various modes have been successfully fabricated, such as Janus microspheres, microtubular microrockets and nanowires, etc. These micro/nanomotors have been widely used in different fields of cancer research, as evidenced by significant breakthroughs in the development of a series of intracellular delivery systems, novel diagnosis methods and imaging strategies. In this review, we mainly focus on the tremendous inspiration and opportunities offered by micro/nanomotors in intelligent cancer diagnosis and therapy. Firstly, we demonstrate the recent progress of micro/nanomotors in the fields of cancer diagnostics(ranging from isolation of circulating tumor cells to detection of cancer related biomarkers, such as protein and microRNA), cancer-target delivery(such as drug, interfering RNA, etc.), as well as tumor phototherapy. The challenges and outlooks of micro/nanomotors for future development are also discussed.

Contents

1 Introduction

2 Cancer diagnosis

2.1 Chemical field-driven micro/nanomotor for detection of circulating tumor cells(CTC)

2.2 Physical field-driven micro/nanomotor for detection of intracellular tumor-related biomarkers

3 Targeted drug delivery

3.1 Chemical field-driven motor assist targeted drug delivery

3.2 Physical field-driven motor assist targeted drug delivery

4 Micro/nanomotor-assisted tumor phototherapy

4.1 Photothermal therapy of tumor

4.2 Photodynamic therapy of tumor

5 Conclusion and outlook

Graphical abstract

Keywords

micro/nanomotors / cancer / diagnosis / therapy / intelligent

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Jiajia Wang, Huiying Wu, Renfeng Dong, Yuepeng Cai. Micro/Nanomotors on the Way to Intelligent Cancer Diagnosis, Delivery and Therapy. Progress in Chemistry, 2021, 33(5): 883-894 DOI:10.7536/PC200660

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1 Introduction

Cancer is a serious threat to human health, and has a very high mortality rate in the world because of its early symptoms, difficult diagnosis and poor treatment. According to the World Health Organization (WHO), by 2030, 21 million people will be diagnosed with cancer, and the number of deaths may exceed 13.1 million[1]. Countless scientists and doctors have devoted themselves to the cause of fighting cancer and have made great efforts to this end. At present, many effective methods for the diagnosis and treatment of cancer have been developed and widely used in clinical practice, including chemotherapy, gene therapy, radiotherapy, immunotherapy and phototherapy[2]. However, there are still many problems in the existing cancer diagnosis and treatment strategies, such as the passive movement of detection probes or drugs can not reach the target tumor site in the appropriate time and precise space, which seriously limits the effectiveness of diagnosis, delivery and treatment, resulting in some cancer patients missing the best treatment stage[3,4].
In 1966, a film called "Magical Journey" attracted wide attention, which told the story of five doctors who were reduced to micron size to enter the human body for surgery and escaped from the eyes after completing the task. In this fantastic film, it fully demonstrates the good wish of human beings to use micro/nano technology to solve medical problems accurately in micro or nano space[5]. At present, with the development of nanotechnology, a variety of functional nanomaterials have emerged, such as quantum dots (QDs), gold nanoparticles (AuNPs), hydrogel nanomaterials and so on, which provide more opportunities for further solving the problems faced in the process of cancer diagnosis and treatment[6,7][8][9,10]. However, in order to achieve precise treatment of cancer, these passively running nanomaterials can not fully meet the requirements of precise diagnosis and treatment of cancer due to the lack of precise distribution. Among many nanomaterials, the emergence of micro/nano motors with autonomous motion performance, such as those shown in movies, has brought hope for precise diagnosis and treatment of tumors.
Micro/nano motor is a kind of micro device which can convert all kinds of external energy (light, sound, magnetism, electricity, chemical energy, etc.) Into its own mechanical energy and realize autonomous movement[11,12][13,14][15,16][17,18][19,20]. With the development of nanomaterial synthesis technology, researchers have successfully prepared various shapes of micro/nano motors, such as Janus dihedral structure motor, microtubule motor, linear motor and so on[21⇓~23][24⇓~26][27⇓~29]. These micro/nano motors with different shapes can move autonomously in solution under different driving modes (such as chemical field driving and physical field driving (ultrasonic driving, magnetic driving, etc.)) and different driving mechanisms (bubble driving, thermophoresis, diffusion electrophoresis, electrophoresis, etc.)[30][31][32][33][34][35][36]. In addition, because their size is usually in the nanometer or micron level, they also have the characteristics of micro/nano materials, such as high specific surface area, easy surface modification and so on. After functional modification, these micro/nano motors, which have the advantages of active motion and the characteristics of micro/nano materials, can move autonomously in solutions, cells or tissues. Compared with the traditional passive micro/nano materials, micro/nano motors with active motion are expected to deliver detection probes or drugs to the target location at the appropriate time and precise space, which can better meet the various requirements of intelligent cancer diagnosis and treatment. For example, in the field of detection, due to the advantage of active motion of micro/nano motors, the detection method based on micro/nano motors can improve the efficiency of binding biological probes with targets without external force assistance, and improve the detection performance. In the field of drug delivery, micro/nano motors have great potential in the development of targeted drug delivery systems due to their active and controllable targeting and local release. In order to make the micro/nano motor play a better role in the field of biological applications, it should also have good biocompatibility, low toxicity and other characteristics. Therefore, "intelligent robots" used in nanomedicine usually use non-biotoxic or biocompatible substances as fuel, or choose external field driving methods, such as magnetic driving, electric driving, ultrasonic driving and so on. It is worth mentioning that because tumor cells produce hydrogen peroxide in the process of oxidative stress, the internal environment of tumor cells is acidic.Some micro/nano motors can use hydrogen peroxide or acidity in the local environment of tumor cells to achieve autonomous movement, and further complete tasks through precise positioning, which has incomparable advantages in tumor diagnosis and treatment.
At present, the application of micro/nano motors in cancer diagnosis and treatment has been widely concerned by researchers, and a series of research progress has been made, which proves the possibility of its application in nanomedicine in the future. For example, Wang et al. Have developed a series of strategies for precise treatment of cancer based on motors driven by external fields such as ultrasound and magnetic fields[37,38][39]. In order to better promote the research of functional micro/nanomotors in the field of cancer diagnosis and therapy, this paper mainly focuses on the latest research progress of micro/nanomotors in cancer diagnosis, drug targeted delivery and phototherapy. Firstly, the application and development of micro/nano motors in tumor diagnosis and targeted drug delivery are introduced from the perspectives of chemical and physical fields. Then, the latest progress of micro/nano motors in the phototherapy of tumors is introduced. Finally, the problems and challenges of micro/nanomotors in tumor diagnosis and treatment were discussed based on the practical application requirements, and the application prospects of novel functional micro/nanomotors in clinical medicine were prospected. There is a long way to go, and the clinical application of micro/nano motors in the field of precise diagnosis and treatment of cancer is still facing enormous challenges. This paper aims to promote the exploration of micro/nano motors in the field of tumor detection and treatment by summarizing the existing related research, and further bring new hope for the victory over cancer.

2 Tumor diagnosis

Early detection, early diagnosis and early treatment of tumors are the key to improve the cure rate. However, most cancers do not have obvious symptoms in the early stage, and by the time solid tumors are detected, most have metastasized from the original site, which is the most common cause of death in cancer patients. At present, the traditional cancer diagnosis technology mainly includes medical imaging, related marker detection, tissue biopsy and so on[40]. However, these diagnostic techniques fail to achieve accurate detection in the early stages of most cancers, and suffer from low sensitivity and specificity, so that cancers are usually diagnosed in the late stages with low cure rates. Micro/nano motors with unique advantages of autonomous motion provide new opportunities for accurate diagnosis of cancer. On the one hand, the micro/nano motor can promote the combination of the biological probe and the target without external force by virtue of the characteristic of autonomous motion of the micro/nano motor, and improve the sensitivity and timeliness of detection by improving the combination efficiency of the target; On the other hand, the surface of the micro/nano motor is easy to modify, which provides a greater possibility for improving the specificity of detection. Micro-nano motors can be divided into two categories according to their energy sources: "chemical field-driven" and "physical field-driven". Among them, the chemical field-driven type means that the motor itself catalyzes the surrounding specific substances or directly reacts with the specific substances in the surrounding environment, and is driven by successfully converting chemical energy into its own mechanical energy through the construction of asymmetric environment. The driving mechanisms of chemical field-driven motors mainly include electrophoresis, self-diffusion electrophoresis, bubble driving, etc. At present, researchers have reported a series of diagnostic methods based on micro/nano motors, including tumor cell detection and related biomarker detection (protein, nucleic acid, etc.).

2.1 Chemical-field-driven motor for circulating tumor cell (CTC) detection

circulating tumor cells (CTCs) refer to the tumor cells that shed from the primary tumor and enter the blood circulation, namely, all kinds of tumor cells in the peripheral blood. The detection of circulating tumor cells is an important indicator for the clinical diagnosis of cancer and the evaluation of therapeutic efficacy. Due to its complex environment, the accurate detection of CTC is faced with many difficulties, so the realization of efficient separation and enrichment of CTC is a key step in the accurate detection.
With the development of nanotechnology and nanomaterials, many functional nanomaterials have emerged, among which magnetic nanomaterials with excellent superparamagnetism have attracted wide attention. Magnetic nanomaterials have good magnetic separation properties, which can effectively capture and separate CTCs in complex biological samples. For example, Wen et al. prepared magnetic nanospheres (Figure 1A) through a highly controllable layer-by-layer assembly method. The magnetic nanospheres are stable in nature and will not aggregate or precipitate in whole blood. The immunomagnetic spheres obtained by further modifying antibodies can achieve rapid capture of CTCs, and the capture efficiency is as high as 94% within 5 minutes[41]. In addition, an approved commercial screening system based on magnetic nanospheres has been developed, the CellSearch system, a commercial automated immunomagnetic enrichment technology for CTC detection. Although the CellSearch system has been commercialized, there are still some problems. On the one hand, the capture based on magnetic nanospheres can only be achieved by passive diffusion of fluids, and because the biological environment of blood or tissue has high viscosity, it also needs to be mixed by external force, which makes the process complex and leads to cell loss. On the other hand, magnetic nanospheres are difficult to reach where body fluid circulation can not reach, so they can not play a role. The emergence of micro/nano motors with autonomous motion has brought new opportunities for the separation and detection of CTCs.
Among them, the motor driven by the reaction force of the bubble has a faster speed and a larger traction force, which has attracted wide attention in the field of cell capture and separation. As early as 2011, Balasubramanian et al. Prepared a bubble-driven Ti/Fe/Au/Pt microtubule motor and sputtered a layer of Au on its surface (Fig. 1b) for functional modification to achieve specific capture, separation and detection of tumor cells[42]. It is worth noting that by optimizing the thickness of the Fe layer, the motor prepared by them has good magnetism, and the direction of the motor can be effectively controlled by adjusting the direction of the external magnetic field in complex biological media, so that cells can be captured and separated well. In this study, the speed of the motor was reduced from 85 μm/s to 80 μm/s in the serum environment, which fully proves that the speed of the motor is little affected by the cell load, and a slight reduction in speed is conducive to the effective capture and transportation of cells. Secondly, from the perspective of cell detection, the motor can bypass non-targeted cells to achieve highly specific capture and detection of tumor cells. This study provides a great possibility for the separation and detection of tumor cells in complex biological media, and is expected to directly detect CTC without sample pretreatment.
Although the separation and enrichment performance of microtubule motor is better than that of microsphere motor, it still has some shortcomings in cell capture due to its inherent steric hindrance[43]. The emergence of Janus flexible fiber motor, which can move freely in blood and has a larger specific surface area, provides the possibility to improve the shortcomings in the field of CTC detection[44]. For example, Zhao et al. prepared a novel Janus fiber motor with catalase (CAT) attached to one side to catalyze hydrogen peroxide to drive the motor[45]; The TLS11a aptamer binds to the other side of the Janus fiber to recognize cells and achieve efficient and specific capture. The motor is cleverly modified with TPE-T and FITC-G fluorophores on the side connected with the aptamer, and the two fluorophores are released when the motor captures the tumor cells, and the detection of the tumor cells can be realized by counting the fluorescence color changes caused by the aggregation-induced luminescence effect of TPE and the quenching caused by FITC aggregation before and after the cells are captured. Furthermore, the intensity and area of the interaction between the ligand and the tumor cell receptor can cause changes in fluorescence, and the density of the receptor on circulating tumor cells is related to the stage of cancer development[46,47]. Therefore, this study provides a feasible strategy for rapid and sensitive detection of tumor cells and prognosis development of tumors.

2.2 Physical-field-driven motor for intracellular tumor marker detection

Because of the particularity of cancer, the diagnosis of cancer can not only directly detect tumor cells, but also detect tumor-related biomarkers. For example, alpha-fetoprotein (AFP) is an important biomarker for primary liver cancer, while prostate-specific antigen (PSA) has been used as an effective marker for prostate cancer. Among these tumor-related biomarkers, the expression level of nucleic acids is related to the development and stage of tumors, which makes the detection of nucleic acids of great significance in the effective diagnosis and treatment of clinical cancer[48]. Traditional detection methods, such as quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), involve complex steps such as nucleic acid extraction and amplification, and require specific amplification instruments, which are cumbersome and inefficient. With the development of nanotechnology, some nanomaterials with excellent properties have emerged, such as quantum dots, gold nanoparticles and magnetic nanoparticles, and some detection methods based on these nanomaterials have been reported[49,50][51,52][53]. However, these methods face the problem of low detection efficiency when realizing the in situ detection of intracellular biomarkers. The emergence of micro/nano motors with autonomous motion characteristics provides more possibilities to overcome the problems in the past nucleic acid detection.
Unlike chemical field-driven motors, physical field-driven motors can actively move under external stimulation without considering the problem of toxic or exhausted fuel, which can be divided into magnetic drive, optical drive, ultrasonic drive and so on according to the type of external stimulation.Among them, the ultrasound-driven motor has ultra-fast speed, significant propulsion and good biocompatibility, and can mechanically interact with cells to achieve deep tissue penetration[54]. Ultrasonic driven motor has been widely studied in the field of intracellular tumor markers detection because of its unique advantages and continuous movement in living cells. For example, Qualliotine et al. prepared a rhodamine (FAM) -ssDNA functionalized gold nanowire motor, which can move flexibly in complex biological media under the drive of ultrasonic field[55]. The obtained motor probe is mixed with tumor cells, when the target mRNA exists in the cells, the fluorescence of the FAM is recovered, and the in situ real-time detection of the intracellular mRNA can be realized by counting the intensity of the fluorescence. This study provides a novel and feasible strategy for real-time detection of HPV-OPC, and further demonstrates the effectiveness and generalization of the first "OFF-ON" fluorescence sensing intracellular nucleic acid detection strategy based on micro/nano motors[56]. Secondly, by changing the sequence of ssDNA probe and designing multiple signal-labeled probes, this method is expected to be used to detect a variety of different mRNAs, which has good versatility. This micro/nanomotor-based nucleic acid detection method provides a new option for the detection of tumor nucleic acid in the future.
In different tumor biomarkers, the expression level of AIB1 protein reflects the occurrence and development of breast cancer to a certain extent, and the conventional methods for detecting AIB1 protein in cells or tissues are mainly immunohistochemical analysis or Western blot analysis[57][58]. Now, inspired by the "OFF-ON" fluorescence sensing strategy, an efficient method for detecting AIB1 protein has been successfully developed based on ultrasound-driven nanomotors (Figure 2).It opens up a new horizon for the early clinical diagnosis of breast cancer, and further shows that this micro/nanomotor-based detection method has great potential in the future clinical in situ detection of various cancer biomarkers[59].

3 Targeted drug delivery

Drug targeted delivery plays an important role in many cancer therapies. However, the traditional drug delivery system only relies on body fluid circulation, which has the problems of off-target, high dosage, poor permeability and large clinical side effects. For example, doxorubicin (DOX) is an anti-tumor drug commonly used in cancer treatment, but the traditional delivery system has side effects such as cardiotoxicity, which may lead to congestive heart failure in patients years after treatment[60][61,62][63]. Therefore, for patients with heart disease, the seriousness of this side effect can be imagined. With the development of nanomaterials, some novel drug delivery strategies based on nanomaterials have been proposed. Among them, the drug delivery strategies based on liposomes and polymer nanoparticles have attracted wide attention, and the delivery systems based on liposomes, such as Doxil and Myocet, have been approved by FDA due to their advantages of low side toxicity. However, although these passive drug targeting systems extend the drug circulation time and enhance the permeation and retention effects, they all have different problems. For example, Doxil delivery system can cause toxicity to skin due to liposome leakage and other factors, and nanoparticles are easy to accumulate in off-target areas such as lung[64][65]. Therefore, there is an urgent need for a drug delivery system with high efficiency and low side effects. Micro/nanomotors have great potential in the development of targeted drug delivery systems due to their active and controllable targeting and local release.

3.1 Chemical-field-driven motor assist targeted drug delivery

Chemical field-driven motors can be delivered in vivo by catalyzing naturally occurring compounds in the body to obtain power for autonomous movement. Therefore, chemical field-driven motors with unique advantages have been widely used in targeted drug delivery. For example, some micro/nanomotors can use the local high level of hydrogen peroxide produced by cancer cells to power their own movement and achieve effective penetration and precise drug release[66]. For example, it has been reported that targeted drug delivery can be achieved by preparing Pt/CaCO3@HA-CB[6] nanomotors with Janus structure to catalyze the decomposition of hydrogen peroxide to provide power for itself[67]. Because the tumor site is weakly acidic, when the motor reaches the tumor site, the CaCO3 in the motor will respond to pH stimulation and degrade, thus releasing the drug-loaded HA-CB [6] nanogel. At the same time, due to the over-expression of HA receptor in cancer cells, HA-CB [6] nanogels loaded with drugs can be precisely positioned through the targeting ability of HA nanogels to cancer cells, and further achieve precise drug delivery through HA receptor-mediated endocytosis. The whole process is shown in Figure 3. This ingenious design makes the strategy have the targeting ability of dual stimulus response, further improves the accuracy of drug targeted delivery by motor, and effectively avoids the toxic and side effects caused by off-target.
Human gastric juice contains gastric acid, and some micro/nano motors based on Zn, Mg and other metals can react with gastric acid to produce hydrogen to achieve autonomous movement, thus achieving targeted drug delivery in the stomach[68,69][70,71]. Among them, the more active metal Mg can react with water to generate hydrogen to drive the motor, and many drug targeted delivery strategies based on this motor have been developed. For example, Wu et al. ingeniously designed and prepared a bubble-driven micromotor encapsulated in a microcapsule, and used photoacoustic computed tomography (PACT) imaging technology to achieve localization and targeted delivery in mice[72]. The micromotor encapsulated in a microcapsule can be protected from the erosion of gastric juice, and the Parylene layer in the structure is used for maintaining the geometric shape of the motor so as to ensure the stability of the movement of the motor.The Au layer can improve the depth of imaging by enhancing the light absorption of PACT imaging, and can effectively convert near-infrared light into heat after reaching the target position, so that the capsule disintegrates and releases drugs. Researchers have also fully proved that its structure has excellent biocompatibility and degradability through verification experiments. It is worth noting that this method can achieve real-time observation of the position of the capsule in vivo through PACT. When the capsule reaches the target position, under the irradiation of near-infrared light, the capsule ruptures to release and activate the motor encapsulated inside. The autonomous movement of the motor is used to extend the drug retention time, so as to achieve accurate and effective drug delivery. Due to its advantages of excellent depth imaging, precise control and good biocompatibility, the delivery system is expected to be applied to the targeted therapy of gastrointestinal diseases such as colon cancer in vivo, which will expand a new means for the development of real-time, precise and efficient drug targeted delivery system in the future.
In addition to the available acidic environment, there are many substances in the body that can be used as fuel to drive motors, such as urea, glucose and so on. Llopis-Lorente et al. designed and prepared urease catalyzed mesoporous silica nanomotors, and successfully achieved targeted drug delivery. The preparation process and delivery principle are shown in Figure 4A and B respectively[73]. The surface of the mesoporous silica nanoparticle of the motor is covered with a supramolecular nano valve while the mesoporous silica nanoparticle of the motor is loaded with a drug, the supramolecular nano valve can be opened only under an acidic condition, and urease is modified on the surface to catalyze urea to serve as power of the motor. This study skillfully utilizes the potential of mesoporous silica nanoparticles to design nano-valves, and combines with acidic stimulation at tumor sites to achieve enhanced intracellular drug release, which well avoids the side effects of non-targeted drug release due to the unblocked pores of mesoporous silica.
Considering the complete biocompatibility, Tang et al cleverly modified the surface of natural platelet cells with urease, and turned the natural cells into functional micromotors for autonomous movement, so as to achieve targeted drug delivery[74]. It is worth mentioning that its asymmetry brings two advantages. On the one hand, unlike non-Janus platelets, which are completely covered with urease, Janus structures can achieve stronger directional propulsion and more active movement. On the other hand, the effect of urease modification on the functional surface proteins of platelets is negligible, so that the intrinsic biological functions of platelets are preserved and effective binding to target cells (such as tumor cells and bacteria) is achieved. Due to the high concentration of urea in urine, urease-based Janus platelet micromotors are expected to be directly applied to intravesical drug delivery for the treatment of bladder cancer. More importantly, the Janus modified cell surface enzyme strategy developed in this study has a strong generalization, which can be extended to other types of natural cells such as immune cells, red blood cells, stem cells or engineered cells such as CART cells, and can also be extended to other enzymes, pointing out the direction for the development of fully biocompatible intelligent micro/nano motors.

3.2 Physical-field-driven motor-assisted targeted drug delivery

As mentioned above, due to the unique driving mode, the motion of the physical field-driven motor has the following characteristics: it does not need to rely on fuel, it can effectively move in the complex biological environment with high viscosity or high ionic strength, and it has good biocompatibility and strong controllability, which makes it widely used in the field of targeted drug delivery. As early as 2012, Gao et al. First designed and prepared a magnetic field-driven nanomotor for targeted drug delivery, and its structure is shown in Figure 5A[39]. Driven by the magnetic field, the motor picks up the magnetic polymer microspheres loaded with drugs through magnetism, and can combine with HeLa cancer cells and release drugs through the guidance of the magnetic field. This study is the first to study the basic mechanism and impact of cargo loading theoretically and experimentally, and lays a foundation for biocompatible magnetic drive motor to assist drug targeted delivery. In addition to a single magnetically driven motor for targeted drug delivery, cells with the ability to interact with other cells, high biocompatibility and other advantages also have great potential in the design of targeted drug delivery systems. Based on the advantages of sperm, such as high load of anti-cancer drugs and effective protection of drugs, Xu et al designed and developed a magnetic control sperm hybrid motor assisted drug delivery system (Fig. 5B)[75]. After the sperm-mixing motor loaded with the anticancer drug is guided to the tumor cells by the magnetic field, the magnetic quadrangular frame in the structure of the sperm-mixing motor bends and simultaneously releases the sperm in situ, and the sperm can further fuse with the cancer cells to realize drug delivery. As mentioned above, based on the natural advantage that sperm can fuse with cells to effectively deliver drugs, the sperm hybrid motor has great application potential in the treatment of cervical cancer and other gynecological diseases.
Near-infrared (NIR) light, as another physical stimulus, has been widely used in the biomedical field due to its weak tissue absorption and deep penetration into biological tissues, and the motor-assisted drug delivery system driven by NIR light has shown more prominent application potential in the medical field. A large number of studies have shown that Au has a good photothermal effect, so most of the micro/nano motors are driven by near-infrared light combined with Au. Jiao et al. prepared Janus nanomotors by sputtering Au on mesoporous silica nanocarriers, which fully combined the high loading capacity of mesoporous silica carriers with the high cell penetration capacity driven by near-infrared to achieve deep tumor penetration and drug delivery[76]. Ingeniously, it uses the characteristics of oxidative stress in cancer cells to achieve controlled release of drugs through hydrophilic and hydrophobic design switches. The motor itself is a hydrophobic channel, but it will be transformed into a hydrophilic channel in a certain concentration of ROS, thus releasing anti-cancer drugs. As mentioned above, tumor cells have a certain concentration of ROS in their environment due to oxidative stress, so they can achieve precise drug release. Moreover, the surface of the motor is modified with folic acid (FA), which can help the motor effectively identify and attach to the tumor cell membrane, achieve targeted delivery, and effectively reduce the toxic and side effects of drugs. This strategy effectively integrates the functions of high loading, active targeting, high penetration and switch-controlled release, which provides a new idea for the development of multi-functional drug delivery systems in the future.
As a common physical stimulus, ultrasound is also often used in biomedical fields, such as B-mode ultrasound and ultrasound therapy. Therefore, it is undoubtedly feasible to use ultrasound to drive micro/nano motors for biomedical applications. In 2012, Wang et al. First discovered that ultrasound at a certain frequency could drive the movement of metal nanowires, and proved their rotation, self-assembly into metal rod chains and other motion behaviors through experiments, as shown in Figure 6a[77]. Unlike the limitations of chemical driving methods, this research has stimulated the potential of using ultrasonic driving motors in complex biological environments. Further studies have found that ultrasound-driven micro/nano motors can achieve effective delivery through cell membranes without causing significant toxicity, which has attracted wide attention in biomedical applications such as drug delivery therapy. Wang et al. Developed a novel ultrasonically driven motor for drug delivery by combining porous gold nanoparticles and multi-metal nanowire structures (Fig. 6B)[38]. Due to the combination of porous gold nanoparticles, the motor not only has high drug loading capacity, but also can control the release of drugs by near-infrared light. The drug delivery system can realize rapid and effective drug delivery, and provides a new method for clinical treatment. In addition to drug delivery, ultrasonically driven motors have also been used for siRNA delivery to achieve tumor therapy by inhibiting the expression of the corresponding protein. Under the action of ultrasound, the motor modified with siRNA-DNA could enter the cell in a short time and further inhibit the expression of mRNA, which resulted in the disappearance of green fluorescence in the cell to prove the efficient delivery of siRNA (fig. 6C)[78]. Comparative experiments show that ultrasound-driven gold nanowires can effectively promote the intracellular delivery of siRNA, improve the efficiency of gene silencing, and further improve the problems of low efficiency of previous gene silencing strategies.

4 Motor assisted phototherapy of tumor

Tumor phototherapy includes photothermal therapy (PTT) and photodynamic therapy (PDT). Simply speaking, photothermal therapy (PTT) is to use photothermal absorbers with high photothermal conversion efficiency to convert light energy of near infrared light (700-960 nm) into heat energy, and to kill tumor cells by generating local high temperature[79⇓~81]. Photodynamic therapy (PDT) is based on the destruction of microvessels in tumor tissues by ROS produced by photoactivation of photosensitizers, resulting in ischemia and hypoxia, and activating immune response mechanisms, leading to apoptosis of tumor cells[82⇓~84]. With the development of motor synthesis technology, micro/nano motors with autonomous motion advantages provide an opportunity to improve some problems in traditional cancer phototherapy. Through ingenious design, the micro/nano motor can be used to realize the efficient targeted delivery of photosensitizers. Moreover, micro/nano motors have the natural advantages of nanomaterials, which can gather at the tumor site through EPR effect, and can effectively penetrate the biological barrier in combination with the characteristics of autonomous movement, thus achieving deep penetration and effectively improving the efficiency of phototherapy. Today, significant progress has been made in light therapy based on micro/nanomotors, providing more options for the development of specific and personalized nanomedicine.

4.1 Photothermal therapy of tumor

Photo-thermal therapy based on micro/nano motors can achieve precise targeted therapy, which has little impact on adjacent normal tissues and effectively reduces side effects while improving the therapeutic effect. In many photothermal materials, gold nanoparticles can not only convert the absorbed light energy into heat through electron-photon collision, but also dissipate heat energy through its own Brownian motion and collision with the surrounding medium, thus having excellent photothermal effect[85][86]. Based on gold nanoparticles, Yang et al. prepared a star nanomotor driven by near-infrared light for photothermal therapy of tumors, as shown in fig. 7 (a)[87]. Unlike the Brownian motion of pure gold nanoparticles, the nanomotor can move autonomously under the irradiation of near-infrared light based on the temperature gradient on both sides, which makes the collision with the surrounding medium more intense and dissipates more heat energy to further enhance the PTT effect. In this study, the nano-motor with autonomous motion is used to achieve photothermal therapy of cancer cells, which effectively avoids the impact on normal tissues and provides a new way to improve the problems in traditional photothermal therapy.
Due to the influence of biological adhesion, synthetic motors will encounter the problem of speed reduction or even immobility in complex biological environments. In order to improve the biocompatibility of the motor, Xuan et al. cleverly designed and successfully prepared a Janus mesoporous silica nanomotor coated with macrophage cell membrane (MPCM), which can move autonomously under the action of near-infrared light due to the presence of gold coating (Fig. 7B)[88]. In this study, they experimentally demonstrated that the MPCM-coated motor showed excellent motion performance and photo-thermal conversion ability. In biological media, the motor based on MPCM film camouflage can effectively avoid the impact of biological media adhesion, and significantly improve the speed of the nano-motor in biological media. Moreover, the MPCM membrane can further improve the active targeting ability of the motor by specifically recognizing cancer cells. Under the action of near-infrared light, the motor can efficiently enter the tumor and kill cancer cells by enhancing the photothermal effect. The biofunctional micro/nanomotors based on natural cell membranes have good biocompatibility, excellent anti-bioadhesion ability in biological media, and active targeting of cancer cells, which provide more ideas for the future design of intelligent robots applied to biological environments.
In addition to enhancing the biocompatibility of the motor by utilizing the camouflage of natural cell membranes as described above, Choi et al. prepared a buccal nanomotor for photothermal therapy of tumors by encapsulating Pt NPs and NC with PEG44-b-PS141[89]. The motor moves autonomously through the decomposition of hydrogen peroxide catalyzed by Pt, while NC, as a highly efficient near-infrared light absorber, can heat up to more than 55 ℃ under the irradiation of near-infrared light to dehydrate PEG, resulting in the aggregation of the motor and the reduction of its speed. When the near-infrared light is turned off, the PEGs in the motor separate due to rehydration and return to the pre-heating speed. Therefore, the temperature response behavior excited by the near-infrared light is reversible, and the controllable movement of the nano-motor can be realized. Furthermore, the motor showed active targeting movement by catalyzing the hydrogen peroxide released by tumor cells, and finally killed the tumor cells under near-infrared light irradiation (Fig. 7c), which further demonstrated the feasibility of realizing photothermal therapy based on micro/nano motors.

4.2 Photodynamic therapy of tumor

Photodynamic therapy (PDT) is different from radiotherapy and other cancer treatment methods, which has a selective degree of damage to tumor cells, less toxic side effects and less trauma, and has become a very promising means of cancer treatment. At present, although PDT has been officially approved for application, it still faces some problems in clinical application, such as severe hypoxia at the tumor site and poor photosensitizer (PS) selectivity[90,91][92,93]. Insufficient oxygen supply to the tumor can seriously reduce the photodynamic effect of photosensitizers, thereby affecting the efficacy of photodynamic therapy. The poor selectivity of photosensitizers will pose a threat to normal tissues and increase toxic and side effects. Therefore, in order to further improve the efficacy of photodynamic therapy, targeted delivery system can be designed to deliver oxygen and photosensitizer accurately at the same time, so as to solve the problem of local hypoxia of tumors. Targeted delivery in complex biological environments requires the delivery system to have the following characteristics, such as autonomous movement, controllable direction of movement, good biocompatibility, efficient ability to carry oxygen and photosensitizers, and avoidance of immune clearance in blood circulation. The advent of micro/nano motors opens up the possibility of designing such delivery systems.
Gao et al. ingeniously designed and fabricated a micromotor coated with erythrocyte membrane (Fig. 8A), which has a high-density biconcave disk-like structure. This high-density and asymmetric disk-like structure can effectively convert ultrasonic energy into kinetic energy and enable the motor to move autonomously[94]. At the same time, the motor is wrapped with Fe3O4 magnetic nanoparticles, so the direction of the motor can be controlled by adjusting the direction of the magnetic field. Therefore, the motor can achieve active targeting delivery to tumor cells under the dual control of ultrasound and magnetic field. In addition, the existence of the erythrocyte membrane on the surface of the motor endows the motor with good biocompatibility, so that the motor can effectively avoid immune clearance and biological adhesion, and still has lasting motility in a complex biological environment. This study fully proved that the motor has good ability to carry oxygen and photosensitizer through HeLa cell activity and cell parameters, and its photodynamic effect can quickly kill cancer cells and effectively enhance the efficacy of photodynamic therapy (Fig. 8B). This multifunctional motor not only has great potential for photodynamic therapy of cancer in the future, but also provides new insights for targeted drug delivery therapy.
Starting from the development of a multi-functional platform for synergistic therapy, You et al. Successfully prepared enzyme-modified UCNP @ MOF core-shell nanomotors, which can improve the therapeutic efficiency by enhancing the synergistic effect of PDT and starvation therapy (ST)[95]. The motor is simultaneously modified with catalase and glucosidase, wherein the catalase can catalyze and decompose hydrogen peroxide naturally existing in the tumor cell environment, and the glucosidase can catalyze and decompose glucose to generate extra hydrogen peroxide so as to provide power for the movement of the motor. After entering cancer cells, the UCNP in the motor structure can convert near-infrared light into blue light to excite the photosensitizer loaded in the porous shell of ZIF-8 to achieve effective photodynamic therapy. In addition, the glucose enzyme on the motor can inhibit the growth and activity of malignant tumor cells by consuming the glucose in the malignant tumor cells to achieve ST, and one of the catalytic decomposition products, hydrogen peroxide and inherent hydrogen peroxide, can be decomposed to produce oxygen under the action of catalase.This can not only solve the problem of tumor cell hypoxia to enhance the efficacy of PDT, but also promote the consumption of intracellular glucose to enhance the efficacy of ST. This virtuous circle and synergy caused by the dual enzyme reaction effectively enhances the efficacy of PDT and ST, which provides a new vision for the future development of micro/nano motors with synergistic therapeutic effects.

5 Conclusion and prospect

As a frontier product of nanotechnology development, micro/nano motors with unique motion advantages have emerged in the field of cancer diagnosis and treatment. In this paper, we first summarize the application progress of micro/nanomotors in cancer detection and targeted drug delivery from the perspectives of chemical field driving and physical field driving, and then summarize the latest research progress in the field of cancer phototherapy. With the advantages of micro/nano motors, a series of new tumor diagnosis methods and multi-functional drug targeted delivery systems have been developed, which prove that micro/nano motors have great potential for clinical application of precise cancer treatment in the future. However, there are still many problems in the field of micro/nano motors, which need to be further explored.
In order to effectively improve the cure rate of cancer, accurate diagnosis of early cancer is particularly important. However, at present, tumor diagnosis methods based on micro/nano motors are mainly judged by the change of speed or fluorescence signal. Among them, the measurement of fluorescence signal is easy to fluctuate due to the influence of instruments and environmental factors, and because complex biological media often have strong autofluorescence background, it is also easy to encounter the problem of insufficient fluorescence detection signal[96]. In addition, most of the reported micro/nano motors are not versatile because they only incorporate one detection probe. Therefore, in order to better meet the detection needs in complex biological environments, micro/nanomotors effectively combined with other new functional nanomaterials may provide a new vision for the development of universal and highly sensitive biological probes.
At present, the biggest advantage of using micro/nanomotors to develop targeted drug delivery systems is that they can move autonomously and deliver drugs precisely, while most of the reported micro/nanomotors are composed of inorganic materials, which may still have serious immunogenicity and the largest tolerated dose. Secondly, in order to effectively pass through the blood stream or enter cells, the size of the motor used to deliver drugs should also be strictly controlled, ideally between 10 and 100 nm. Although the physical field driven motor is widely used because it does not need fuel, it may still have potential dangers, such as the application of ultrasound may lead to tissue damage, and the harm of electromagnetic waves to human health is still under study and there is no clear conclusion[97][98⇓⇓~101]. In addition, at present, the application of micro/nanomotors in phototherapy of tumors usually relies on small rodents such as mice, and the research time is short (usually less than 3 months), while in order to better clinical application, the long-term toxicity and stability of micro/nanomotors should be concerned. Therefore, in order to achieve safer clinical application of cancer therapy, it is necessary not only to comprehensively evaluate the system designed based on micro/nano motors, but also to establish appropriate animal models for application research to correctly guide future clinical application. To this end, collaboration with other specialized fields, such as biochemistry or oncology, may provide new insights into the development of micro/nanomotors that meet the requirements of clinical applications.
In addition, there are still many difficulties to be overcome before the micro/nano motor is finally put into clinical application. When micro/nano motors enter the human blood circulation system, most of them will encounter problems such as blood fouling, immune clearance, blood flow resistance and so on, which will greatly hinder the implementation of their diagnostic or delivery tasks. Moreover, because tumor diagnosis, delivery and other tasks require a large number of micro/nano motors to complete, how to effectively control the movement of a large number of micro/nano motors is particularly critical. Therefore, the preparation of micro/nano motors with multiple functions, such as self-driving, intelligent carrier, in-situ real-time positioning and precise control, is expected to bring hope for this research.
Although there are still many challenges in the application of micro/nano motors in the field of cancer diagnosis and treatment, they are still in rapid development. With the further development of interdisciplinary cooperation, we believe that functional motors with unique advantages will provide a powerful means for future cancer diagnosis and treatment.

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Funding

National Natural Science Foundation of China(21671071)

National Natural Science Foundation of China(21805096)

Guangdong Provincial Science and Technology Project(2017B090917002)

Guangdong Provincial Science and Technology Project(2019A050510038)

Guangdong Provincial Science and Technology Project(2019B1515120027)

China Postdoctoral Science Foundation(2019M662948)

South China Normal University Young Teachers Research and Development Fund(18KJ13)

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