Biosensors and Bioelectronics 222 (2023) 114960

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Biosensors and Bioelectronics

journal homepage: www.elsevier.com/locate/bios

Magnetic Micro/nanorobots for biological detection and targeted delivery

Xue Deng a, Yuan Su b, Minghao Xu a, De Gong d, Jun Cai d, Muhammad Akhter e, Kehan Chen a,
Shuting Li b, Jingwen Pan a, Chao Gao a, Daoliang Li e, Wenqiang Zhang a, *, Wentao Xu b, c, **
a
College of Engineering, China Agricultural University, Beijing, 100083, China
b
Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health Institute of Nutrition and Health, China Agricultural University, Beijing,
100083, China
c
Key Laboratory of Safety Assessment of Genetically Modified Organism Food Safety MOA, College of Food Science and Nutritional Engineering, China Agricultural
University, Beijing, 100083, China
d
School of Mechanical Engineering and Automation, Beihang University, Beijing, 100191, China
e
College of Information and Electrical Engineering, China Agricultural University, Beijing, 100083, China

A R T I C L E I N F O

Keywords:
Magnetic micro/nanorobot
Functionalization
Detection
Targeted delivery

Micro/nanorobots can effectively convert a variety of energy sources 1. Introduction

into power, thereby providing highly effective resources for human
beings at the micro/nanoscale. Magnetic micro/nanorobots have Rapid developments in all facets of life have introduced various
attracted significant attention, particularly in the fields of biological harmful substances that significantly threaten human health and the
detection and targeted delivery, based on their unique motion charac­ environment. Such substances include excessive and prohibited food
teristics, non-damaging penetration through biological tissues, and additives, pesticide residues, heavy metals (e.g. lead, mercury, and
wireless remote control manipulability. In recent years, progress in the cadmium), and a plethora of pathogenic microorganisms (Cesewski and
design, manufacturing, and operation of magnetic micro/nanorobots Johnson, 2020; Zhang, Y. et al., 2019). Therefore, the rapid, sensitive,
has significantly promoted their functional integrity and applicability, and specific detection of harmful substances is essential for quantitative
and demonstrated their significant potential for biomedicine. This re­ analysis and monitoring. Conventional detection methods include liquid
view summarises the latest applications and future development pros­ chromatography, gas chromatography-mass spectrometry, and immu­
pects of magnetic micro/nanorobots in the fields of biological detection noassays (Cacciola et al., 2017; Yao et al., 2020). These methods offer
and targeted delivery. The concepts of connotation, driving modes, and good stability with high selectivity and detection accuracy. However,
functional strategies of magnetic micro/nanorobots are also introduced. most methods require advanced detection equipment, laboratory-based
Finally, the potential advantages and future research directions of instruments, and professional and technical personnel, and have low
magnetic micro/nanorobots are discussed, providing clear evidence that detection efficiency and a low degree of automation. Consequently, re­
the progressive integration of robots, detection, medicine, and other searchers have been committed to developing new devices, systems, and
technologies will have a significant impact on future biomedical technologies for the detection of harmful substances (Agrahari et al.,
applications. 2020; Alapan et al., 2019). Among these novel developments, magnetic
micro/nanorobots (Bente et al., 2018; Yan et al., 2019) have enabled the
design and introduction of alternative detection modes in the field of
detection technology, providing advantages such as high sensitivity,

* Corresponding author. College of Engineering, China Agricultural University, Tsinghua East Road 17, Beijing, China.
** Corresponding author. Laboratory of precision nutrition and food quality, Department of Nutrition and Health, China Agricultural University, Tianxiu Road 10,
Beijing, China.
E-mail addresses: [email protected] (W. Zhang), [email protected] (W. Xu).

https://doi.org/10.1016/j.bios.2022.114960
Received 23 April 2022; Received in revised form 12 October 2022; Accepted 25 November 2022
Available online 28 November 2022
0956-5663/© 2022 Elsevier B.V. All rights reserved.
X. Deng et al. Biosensors and Bioelectronics 222 (2023) 114960

high selectivity, and batch production. micro/nanoscale robots and micro/nano operation robot systems. In
Inspired by complex micro/nanoscale structures and the adaptive particular, when micro/nanorobots have magnetism, they are referred
functions of natural organisms, researchers have designed and manu­ to as magnetic micro/nanorobots.
factured numerous micro/nanoscale functional devices. Progressive
developments in micro/nanomanufacturing technology and nano­ 2.2. Common types
science have led to unprecedented opportunities for the design and
fabrication of fine, smart, and high-sensitivity micro/nano functional The microscopic scale, diversified functional structures, and precise
devices. Considering their immense potential as detection tools and the control characteristics of magnetic micro/nanorobots make them
impact of harmful molecules on detection, researchers have conducted perfectly suited to meet the needs of biological detection and targeted
many studies on their structural design, driving mechanisms, forming delivery. Many researchers have drawn inspiration for the design and
and manufacturing, and practical application (Lee et al., 2021; Xu et al., manufacture of magnetic micro/nanorobots from the movement be­
2020; Bente et al., 2018; Chen et al., 2017), including biological haviours or modes of various microorganisms or animals in nature.
hybridisation, tracking, in vivo positioning, and motion control. Various Common examples include flexible nanowires (Jang et al., 2015; Wu
manufacturing strategies can achieve different motion behaviours and et al., 2021), spiral microswimmers (Chen et al., 2017a; Yan et al.,
functional characteristics (Nguyen et al., 2021; Zhang, Y. et al., 2019). 2015), spherical micro/nanorobots (Xie et al., 2019; Alapan et al.,
Micro/nanorobots can be powered by light (Sipova-Jungova et al., 2020), and more specialised types of structures (e.g. biological hybrid
2020), ultrasonic waves (Lu et al., 2019; Meng et al., 2020), electricity micro/nanorobots and magnetotactic bacteria), as shown in Fig. 1.
(Si et al., 2020), magnetic power (Li, J. et al., 2020), chemical fuel, Although their applications in biological detection and targeted delivery
thermal gradients, and external or exogenous energies, or their combi­ are still in their infancy, magnetic micro/nanorobots have exhibited
nation (Chen et al., 2018; Park et al., 2021; Wang, J. et al., 2020). To outstanding potential as invaluable future resources.
achieve the detection and timely disposal of harmful substances in
blood, urine, or other complex samples and environments, researchers 3. Driving modes of magnetic micro/nanorobots
are continually exploring new and increasingly efficient methods for
solving these problems and introducing innovations in the design and 3.1. Magnetically driven micro/nanorobots
process preparation of bionic magnetic micro/nanorobots (Ji et al.,
2019; Kim et al., 2020; Wu et al., 2019), including tubular, spherical, Compared to traditional driving modes, the excellent remote and
helical, and nanoscale structures. Depending on the inherent structure, wireless control characteristics of external magnetic fields allow mag­
performance, semi-intelligence, and operability of these magnetic netic micro/nanorobots to perform more complex tasks and navigate
micro/nanorobots (Zhang, Y. et al., 2019), they can be used in appli­ through tissues and narrow areas of the human body that are difficult to
cations in many fields, including biomedicine (detection and diagnosis, enter manually. Magnetic resonance imaging has shown that magnetic
drug/cell delivery and targeted therapy of solid tumours, and smart drug fields are harmless to cells and other tissues in clinical applications
carriers or microsurgery tools) (Li et al., 2017; Yang et al., 2020a; Dai (Zhang et al., 2019). Thus far, there have been many studies on rotating
et al., 2021) and ecological environments (governance and repair) (Gao magnetic field (Niedert et al., 2020), oscillating magnetic field, and
and Wang, 2014). gradient magnetic field. In 2020, Magdanz et al. developed a biological
To give full play to their potential, the functionalisation of multiscale hybrid magnetic microrobot through the electrostatic self-assembly of
structures and utilisation of micro/nanoscale smart materials are sperm cells and magnetic nanoparticles (Magdanz et al., 2020). The
essential for the functionalisation of magnetic micro/nanorobots, espe­ flexibility and echo characteristics of the microrobots were guaranteed
cially those used in biomedical detection and targeted drug delivery. by coating magnetic nanoparticles onto the surfaces of bovine sperm
Through structural design and optimisation, surface modification, and cells. Under a rotating magnetic field, the microrobots were loaded with
chemical composition, the binding efficiency of magnetic micro/nano­ doxorubicin (DOX) hydrochloride, which are anti-cancer drug mole­
robots with target analytes in complex environments can be improved cules, proving their stability and excellent potential for active drug
(Kim et al., 2020; Zhang, H. et al., 2019) to facilitate their vital roles in capture, transport, and release with minimally invasive imaging and
multi-substance detection and evaluation. Research goals include the positioning. Wang et al. functionally modified a spiral magnetic
detection of specific analytes in blood, urine, and gastric juices, and microrobot with nanoparticles such as Au, Pd, and Fe3O4 for the suc­
mutant proteins in healthy organisms or mycoviruses in food samples cessful loading of DOX (Wang et al., 2019). Experimental results proved
(Baeza and Vallet-Regi, 2018), as well as the treatment and prevention that the synergistic effects of chemotherapy and hyperthermia were
of cancer and cardiovascular diseases. better than those of either chemotherapy or hyperthermia alone when
This review aims to provide an overview of the latest developments renal and oesophageal cancer cells were selected as research objects.
in the applications of magnetic micro/nanorobots for biological detec­ In addition to a rotating magnetic field, an oscillating magnetic field
tion and targeted delivery. Our summary framework is divided into four is another method for driving and manipulating magnetic swimmers, as
parts. First, the concept and common types of magnetic micro/nano­ shown in Fig. 2. Martynenko et al. prepared magnetic fluorescent
robots are briefly described. Next, the driving modes of magnetic micro/ microbeads for the capture and detection of DSM 7513 bacteria. This
nanorobots are introduced and their functional strategies are system­ type of synthetic microrobot was fabricated by combining silver-indium-
atically summarised. The latest research progress on magnetic micro/ sulphide, ternary quantum dots (QDs), superparamagnetic nanoparticles
nanorobots in the fields of biological detection and targeted delivery are (Fe3O4), and porous calcium carbonate particles (Martynenko et al.,
then summarised. Finally, the future research directions and application 2019). The surfaces of the microbeads were functionalized using a
prospects of magnetic micro/nanorobots are examined. biological ligand (Streptococcus pneumoniae antibody). The immuno­
magnetic capture and rapid enrichment of M. pneumoniae were realised
2. Concept connotation and types of magnetic micro/ under the action of a magnetic field. This magnetic ball-shaped micro­
nanorobots robot can be used not only for the detection and capture of pathogens, but
also as a contrast agent for tumour imaging (Xie et al., 2008) and for the
2.1. Concept connotation detection of endotoxins in pathogenic bacteria (Jurado-Sanchez et al.,
2017). Oscillatory motions provide no particular advantages in terms of
In 1959, Richard Feynman, a Nobel laureate in physics, first pro­ speed, particularly in biomedical applications.
posed the concept of micro/nanorobots (Feynman, 1959). Typically, For biomedical targeting and detection, magnetic micro/nanorobots
micro/nanorobots are divided into two main categories: driven by gradient magnetic fields have also made progress in the areas

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Fig. 1. Overview of magnetic micro/nanorobots. (A) Size comparison of micro/nanorobots. (B) Common types of micro/nanorobots. (C) Main applications of
micro/nanorobots.

of pain reduction, risk of infection, and medical trauma. A gradient surface of a microrobot can catalyse the decomposition of hydrogen
magnetic field differs from a rotating magnetic field in that its force is peroxide into oxygen, which provides power for the magnetic micro­
directly employed to drive a micro/nanorobot, whereas a rotating robot. The surfaces of these microrobots are modified using toluene­
magnetic field converts torque into a driving force, which requires that a sulfonyl groups and Fe3O4 magnetic nanoparticles, which can capture
micro/nanorobot meet specific structural design requirements (such as a breast cancer cells and load DOX under the guidance of a magnetic field.
helix). Although gradient magnetic field actuation requires no special When these magnetic microrobots cooperate, they can also realise the
structural design for microrobots, it requires a large magnetic gradient. efficient transportation of larger cancer cells.
Sun et al. developed a gradient-based magnetic microrobot actuation Magnetotactic bacteria (MTB), which can be utilised as natural
system to address this problem. Their system can provide a maximum microrobots, migrate along geomagnetic lines in a movement behaviour
magnetic field gradient of 20 T/m and can be used to drive various known as magnetotaxis (Uebe and Schueler, 2016). These types of
microrobots applied in vivo (Li et al., 2020). In 2019, inspired by the natural microrobots are diverse in shape, with some being rod shaped
nested Matryoshka dolls of Russia, Huang et al. proposed a hydrogel and others being comma, bag, or spiral shaped, as shown in Fig. 2 (F).
microcapsule robot that can move in biological fluids under a gradient Based on their good biological and physical properties, their internal
magnetic field (Huang et al., 2019). In 2020, Xie et al. proposed a bio­ magnetosomes (Yazdi et al., 2018) act as compasses, responding to
mimetic spherical microrobot that uses a magneto-collective to deliver geomagnetic fields and overcoming anisotropy. Taherkhani et al.
and release drugs accurately in a controlled manner, thereby achieving carboxylated nanoliposomes by using Fe3O4 magnetic nanoparticles to
targeted microvascular thrombolysis therapy (Xie et al., 2020). These modify the surfaces of magnetotactic bacteria and carbodiimide func­
studies proved that magnetic micro/nanorobots driven by magnetic tionally to combine liposomes with magnetotactic bacteria effectively
fields can play a significant role in cancer treatment and biomedicine. (Taherkhani et al., 2014). Under a directional magnetic field, thera­
peutic drugs can successfully target the anoxic zone of a solid tumour
through the active infiltration of magnetotactic bacteria, thereby
3.2. Magnetically guided magnetic micro/nanorobots
providing benefits for targeted therapy. In their construction of a
controllable microswimmer that can deliver antibiotics, Sanchez et al.
Magnetic field driving has become the primary method for navi­
confirmed that non-pathogenic magnetotactic bacteria (Magneto­
gating micro/nanoscale materials through the body (Ghosh et al., 2021).
spirillum gryphiswaldense (MSR-1)) can be integrated with drug-loaded
However, researchers have also attempted to change the motion di­
mesoporous silica microtubules (Stanton et al., 2017). By using the
rections and paths of magnetic micro/nanorobots using magnetic
external magnetic guiding ability and swimming force of MSR-1 cells,
guidance for chemical driving and magnetotactic bacteria, as shown in
Biological hybrids were oriented and forcibly pushed into a mature
Fig. 2 (E). As a widely used fuel, hydrogen peroxide can be catalytically
E. coli biofilm. As an active drug delivery system, magnetotactic bacteria
converted by many metals into water and oxygen to form bubbles or
provide more targeted and clinical application potential than
concentration gradients (Kline et al., 2005). Based on the presence of a
single-component microswimmers or passive drug delivery.
magnetic layer, micro/nanorobots can be easily guided under an
external magnetic field. In 2018, Villa et al. proposed magnetic catalytic
multifunctional microcirculation to capture and transport cancer cells
and drugs (Villa et al., 2018). In this design, the platinum layer on the

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Fig. 2. Schematic diagram of magnetic-field-driven and magnetic-field-guided micro/nanorobots. (A) Rotating magnetic field driving; (B) Oscillating magnetic field
driving; (C) Gradient magnetic field driving; (D) Uniform magnetic field driving. (Adapted from ref (Faivre et al., 2018) with permission of Wiley-VCH, copyright
2018.) (E) Magnetically guided chemical driving. (F) Magnetotactic bacteria and other natural microorganisms.

4. Functionalisation of magnetic micro/nanorobots complete many tasks (e.g. embolus-free micromanipulation, targeted
drug delivery) under an external magnetic field, as shown in Fig. 3 (B).
The application of magnetic micro/nanorobots in real biological The speed of different chain-like microrobots varies depending on fac­
environments is more complex than that in homogeneous Newtonian tors such as the chain length, driving frequency, and tilt angle. Zhang
environments (Wu et al., 2020). Therefore, it is necessary to develop and et al. reported a magnetic catalytic nanomotor agglomerate with mag­
expand the range of application and functional strategies of magnetic netic field control and photothermal enhancement, which realised the
micro/nanorobots, as shown in Table 1. The following subsections detail treatment of pollutants at fixed points (Ji et al., 2020). Vyskočil et al.
the functionalisation of magnetic micro/nanorobots from two perspec­ developed a bendable Au/Ag/Ni microrobot, as shown in Fig. 3 (C),
tives (structural self-assembly and surface modification). which can enter and exit the cytoplasm of cancer cells for cutting and
can be reversed and navigated in any direction under a rotating mag­
netic field (Vyskocil et al., 2020). Additionally, when functional groups
4.1. Structural self-assembly and receptors are introduced into nanomotors, proteins, enzymes, and
other specific substances can also be loaded (Dong et al., 2013; Gong
Magnetic micro/nanorobots formed through aggregation, recon­ et al., 2022b), as shown in Fig. 3 (D) (E).
struction, or self-assembly (see Fig. 3) can simulate natural microor­
ganisms with multifunctional characteristics to help humans complete
various complex tasks such as assisted fertilisation, hyperthermia, and 4.2. Surface modification
brachytherapy. Xie et al. reported a swarm of magnetic microrobots in
which the microrobot swarm self-assembled into different ribbon- and The functional modification of magnetic micro/nanorobots includes
chain-like structures (Xie et al., 2019), as shown in Fig. 3 (A). Their good the attachment of chemical functional groups to their surfaces and the
mobility and flexibility allow them to maintain the integrity of their connection of targeted probes/ligand molecules/proteins, as shown in
structure and function (Yigit et al., 2019), and they are expected to Fig. 3 (D). Advanced functions (e.g., targeted therapy, biological

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Table 1
The driving, functionalisation and application of magnetic micro/nanorobots.
Types Propulsion Functional modification Application Reference
mechanism

biohybrid rotating magnetron sputtering platinum plating, bovine sperm cells load molecular cargo doxorubicin Magdanz V et al.
microswimmers magnetic field coated by magnetic nanoparticles (Fe2O3), improve the hydrochloride, minimally invasive imaging (2020)
echogenicity of the organic body and positioning
micromotors Calcein-acetoxymethyl dye manipulation and patterning of cells Lin et al.
(2018a)
microrollers surface sputtering Ni/Au layer, surface functionalized cell active cargo transportation in blood fluid, Yunus Alapan
specific antibody (HER2), functionalized streptavidin, azide- targeting cancer cells et al. (2020)
modified anticancer drug molecule, biotin and APTES modified
microroller
walking magnetic oscillation electrodeposited magnetic Au/Ag/Ni segment push the microbeads and cell aggregates in J. Li et al.
microrobot magnetic field preplanned arrangement (2020)
particle based streptavidin and biotin coated magnetic particles, magnetic/ for nano-scale manipulation and assembly Cheang et al.
microrobots chemical bonding (2017)
magnetic nanoparticles pulsed magnetic Au coated magnetic nanoparticles, thiolated liposome, induce drug release Acharya and
field sulfhydryl coupling Chikan (2020)
hydrogel-based gradient Acrylamide hydrophilic treatment, embedded Fe3O4 drug loading, encapsulation, transportation Huang HW et al.
microcapsules magnetic field nanoparticles, PVP coated and release (2019)
burr-like porous alternating sputtered nickel and titanium coating materials, poly-L-lysine carry, transport and deliver target cells in Li et al. (2018)
spherical microrobot magnetic field (PLL) coating microrobots, labeled by carboxy fluorescein the body
diacetate succinimidyl ester (CFDA-SE)
nanomotor the surface of cellulose nanocrystals precipitated by Fe/Fe2O3 remove clogged plaque in arteries, targeted Dhar et al.
nanoparticles, Palladium nanoparticles modified Fe–CNCs, contaminant/dye repair (2020)
Sputtered Au layer
hydrogel Gelatin)/PVA, load doxorubicin into PLGA particles, hybrid realise drug delivery to the diseased area of Dong et al.
microrobot Fe3O4 nanoparticles enhance magnetic properties, Coating the eye and recovery of magnetic (2013)
smooth liquid layer, 5-fluorouracil nanoparticles
micro motor/swimmer magnetically deposit Ti/Fe/SiO2, Sperm self-assembly, Carboxyethyl silyltriol local anticoagulant function, heparin cargo Xu et al. (2020)
(sperm/red blood guided (abcr) carboxylated microcaps, heparin liposome functionalized delivery
cell) microcapsules
Hypotonic treatment of red blood cells, loading magnetic for imaging diseases, delivering drugs, and Wu et al. (2015)
nanoparticles, CdTe quantum dots nanocrystals, RBC cells monitoring treatment response
loaded with doxorubicin
Janus capsule styrene sulfonate (PSS) and polyallylamine hydrochloride for short-term drug, target-oriented Wu Y. et al.
coating SiO2 surface, enzyme functionalized Janus capsule transportation and remotely control and (2014)
motor, fluorescein isothiocyanate modified polyallylamine salt, release of biological cells and tissues
deposited SiO2 particles, sputtered Cr/Ni/Au layer,
functionalized Au layer with 3-thiopropionic acid ethanol
solution, encapsulated doxorubicin
magnetotactic bacteria liposome carboxylation, carbodiimide activator (EDC/NHS) for intracellular drug delivery, diffusion of Taherkhani
(MTB) activates cells, utilize intermediate reaction to form amide bond, therapeutic drugs to hypoxic areas of solid et al. (2014)
magnetotactic bacteria attached to nanoparticles tumours

detoxification, and fluorescence imaging) can be further integrated into to the surfaces of magnetic nickel/platinum microrobots to capture
micro/nanorobots to expand their range of application, as shown in target protein molecules and transport them to a target location under
Fig. 3 (E) (F). Additionally, nano-functional materials are widely used in guidance from a magnetic field. Wang et al. selectively and rapidly
micro/nanorobots based on their unique optical properties, good captured, separated, and transported target nucleic acids from original
biocompatibility, and catalytic activity. In 2017, Yan et al. bound Fe3O4 biological samples to their target locations using microrobots as trans­
nanoparticles to the surfaces of microalgae and chemically modified port proteins (Kagan et al., 2011). It is worth mentioning that nucleic
them by using functional ligands to expand the image guidance func­ acid aptamers can be combined with different biomolecules with high
tionality of microrobots (Yan et al., 2017). Wang et al. used thio­ affinity and specificity based on their unique three-dimensional struc­
ls/thioethers with different hydrophilic/hydrophobic groups to modify ture, which provides good conditions for the biological functionalization
magnetic spiral microrobots (Wang et al., 2018), as shown in Fig. 3 (E), of micro/nanorobots. Sitti et al. proposed multifunctional erythrocyte
thereby changing their swimming behaviour in aqueous media. In 2021, microswimmers based on biomaterials (Alapan et al., 2018). The actu­
Gong et al. used natural Spirulina as a template and permeabilized the ating organs were functionalized using biotin, which was specifically
Spirulina cells. CuS nanoparticles were deposited efficiently on the modified with a TER-119 antibody. DOX molecules and super­
Spirulina cells using the electroless plating method and then a layer of paramagnetic nanoparticles were subsequently loaded into erythro­
Fe3O4 nanoparticles was coated onto the surface of Spirulina to obtain cytes. Experimental results demonstrated that the deformability of
biohybrid magnetic helical microrobots (Gong et al., 2022a). The erythrocyte microswimmers is determined by the inherent flexibility of
magnetic microrobots not only retained the original excellent charac­ red blood cells, while the non-covalent interaction between biotin and
teristics of Spirulina, but also enhanced their photothermal effects under avidin molecules ensures good stability, thereby providing a novel
the action of a near-infrared laser, which can kill HeLa cells and research concept for drug targeting and other medical applications in
Escherichia coli, providing a novel strategy for biomedical anticancer and vivo. The team also reported a multifunctional microroller that selec­
antibacterial applications. Additionally, the team realized the efficient tively recognises target cells using specific antibodies and is driven and
loading and controlled release of the anticancer drug DOX in magnetic controlled by magnetic force to achieve the delivery of cancer cells in the
helical microrobots based on Chlorella cells (Gong et al., 2022b). blood (Alapan et al., 2020), as shown in Fig. 3 (F). Additionally, mag­
Chemical functional groups (Fig. 4) have a high functionalization netic micro/nanorobots have also been modified using different bio­
loading capacity and conjugation ability, exhibiting good chemical logical components or loads, as seen in Fig. 4 and Table 1.
stability and anisotropy. Miguel et al. connected anti-immunoglobulin G Polycaprolactones (Tu et al., 2017), enzymes, oligopeptide nucleotides,

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Fig. 3. Functionalisation of magnetic micro/nanorobots. (A) Cluster mode of microrobots under an alternating magnetic field (Reproduced from ref (Xie et al., 2019)
with permission of the American Association for the Advancement of Science, copyright 2019). (B) Self-assembly of superparamagnetic particles, motion charac­
terisation, and cargo handling (Reproduced from ref (Yigit et al., 2019) with permission of Wiley-VCH, copyright 2019). (C) Application of Au/Ag/Ni microrobots in
cancer cell microsurgery with time-lapse tracking (Reproduced from ref (Vyskocil et al., 2020) with permission of American Chemical Society, copyright 2020). (D)
Preparation of a nanomotor with nanoparticle directional self-assembly and its cargo transportation process under a magnetic field (scale: 20 μ m, reproduced from
ref (Dong et al., 2013) with permission of American Chemical Society, copyright 2013). (E) Fabrication process of DOX-loaded magnetic helical microrobots
(Reproduced from ref (Wang et al., 2019) with permission of American Chemical Society, copyright 2019). (F) Chemical functionalisation of targeted antibodies and
DOX loaded on Janus microrollers (Reproduced from ref (Alapan et al., 2020) with permission of American Association for the Advancement of Science, copy­
right 2020).

etc. will further expand the functions of micro/nanorobots. functional micromotors modified with different antibody based on
antibody-protein recognition properties to selectively identify and cap­
5. Application of magnetic micro/nanorobots in the field of ture target protein, myoglobin, and thrombin, avoiding the washing step
biological detection in the traditional immunoassay process (Vilela et al., 2014). The func­
tionalized micromotors realized the motion capture and enrichment in
In recent years, magnetic micro/nanorobots have provided a novel ovalbumin and IgG protein buffer solution. And the micromotor func­
approach to detection that differs from traditional physical and chemical tionalized with anti-ovalbumin antibody could achieve the enrichment
detection methods. Their unique functional and structural characteris­ and capture of ovalbumin under 25% of cases, while the
tics provide immense potential for biological detection and targeted antigen-antibody binding efficiency of myoglobin and thrombin was
delivery. 15%. Functional particles with different sizes and shapes were used to
mark proteins, which could realize visual recognition of target proteins
5.1. Magnetic micro/nanorobots for protein detection and effectively avoid enzyme labeling, proving the feasibility of
micromotors in real-time multi-immunodetection of dangerous proteins
It is essential that proteins in the human microenvironment can be and toxin mimics, as shown in Fig. 5 (A). Gluten is usually extracted
accurately detected and expressed as important biomolecules. Common from seeds, flour, paste and other food substrates, which is mainly
pathological diseases such as cancer, and cardiovascular and neurolog­ composed of glutenin and wheat gluten protein. It is a kind plant pro­
ical diseases are typically caused by protein mutations or imbalances tein. The magnetic beads are regarded as spherical magnetic micro­
(Baeza and Vallet-Regi, 2018). Therefore, the emergence of micro/­ robots. In 2022, Parent et al. used anti-gliadin antibody to functionalize
nanorobots has promoted the development of newer, faster, and more magnetic beads and combined with microfluidic chips to develop a new
convenient detection methods. In 2014, Orozco et al. has constructed microfluidic platform that integrates multi-step bioassays and optical

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Fig. 4. Surface modifications of magnetic micro/

nanorobots. (A) Biohybrid bacterial microrobot
functionalized by TER-119 antibodies and biotin
molecules (Adapted from ref (Alapan et al., 2018).
with permission of American Association for the
Advancement of Science, copyright 2018). (B) Arti­
ficial carrier attached to an artificial microrobot
(Chlamydomonas) through covalent interaction
(Adapted from ref (Weibel et al., 2005). with
permission of PNAS, copyright 2005 National Acad­
emy of Sciences). (C) Magnetically driven Janus
microcylinder with a targeting antibody (HER2) and
drug molecule modified to target cancer cells selec­
tively (Adapted from ref (Alapan et al., 2020). with
permission of American Association for the
Advancement of Science, copyright 2020). (D) Mag­
netotactic bacteria functionalize drug-loaded lipo­
somes to form artificial synthetic biohybrids that can
transport drugs.

Fig. 5. Schematic detection applications of magnetic

micro/nanorobots. (A) Micromotor-based multiplex
immunoassay for labeled protein toxins (Adapted
from ref (Vilela et al., 2014). with permission of Royal
Society of Chemistry, copyright 2014). (B) Detection
of sepsis biomarkers (procalcitonin) in blood based on
multifunctional magnetic Janus particles (Adapted
from ref (Russell et al., 2019). with permission of
Elsevier, copyright 2019). (C) DNA-modified mag­
netic nanoparticles for mercury ion and silver ion
detection (Adapted from ref (Miao et al., 2017). with
permission of American Chemical Society, copyright
2017). (D) Magnetic mesoporous nanobottles for the
detection and removal of heavy metal ions (Repro­
duced from ref (Qiu et al., 2021). with permission of
Wiley-VCH, copyright 2021). (E) Lead ion efficient
removal based on biohybrid magnetic helical micro­
robots (Reproduced from ref (Gong et al., 2021). with
permission of American Chemical Society, copyright
2021). (F) Repeatable manipulation process for toxic
heavy metal recycling and removal using GOX
microrobots (Adapted from ref (Vilela et al., 2016).
with permission of American Chemical Society,
copyright 2016). (G) Biosensor detection of myco­
toxin in a magnetic micromotor (Adapted from ref
(Molinero-Fernandez et al., 2018). with permission of
Wiley-VCH, copyright 2018).

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detection based on automatic magnetic bead manipulation. Based on respectively. It had strong selective recognition ability, and the detec­
different microfluidic chip architectures, the team successfully estab­ tion limit could reach 460 nM and 10 nM, respectively (Miao et al.,
lished a complete ELISA protocol with optical detection and realized 2017), as shown in Fig. 5 (C). In 2021, Qiu et al. successfully synthesized
quantitative detection within 1 h. The system has been verified in the asymmetric hollow magnetic mesoporous silica nanobottles based on
field of food safety, and has achieved the immune detection of gluten in the advantages of mesoporous materials such large pore volume (3.6
the dynamic range of 10–30 ppm, showing good sensitivity (2 ppm) and nm) and large specific surface area (613.4 m2/g), which was a novel
specificity (Parent et al., 2022). In 2019, Russell et al. proposed a nanomotor driven by catalase, as shown in Fig. 5 (D). The removal rate
multi-functional magnetic Janus particle, which was modified by anti­ of copper ions in polluted water increased rapidly to 60% in the first 5
biotic proteins and catalase and has good biological specific recognition min, and reached more than 80% after 1 h (Qiu et al., 2021). The
and motion performance. Based on the high surface area and magnetism nanomotor could remove not only copper ions, but also remove lead ions
of Janus particles, the particles could specifically capture and rapidly and chromium ions. After acid treatment, the removal efficiency of
detect procalcitonin, a biomarker for sepsis, in 13 min (Russell et al., heavy metal ions still remained at 90% even if the nanomotors were
2019). Compared with the conventional detection method (1 h), the repeatedly used.
detection time is greatly reduced, and it does not rely on bulky in­ In addition, Gong et al. prepared a biohybrid magnetic spiral
struments and any sample pre-treatment process. In addition, based on microrobot with superparamagnetism and high surface activity based on
catalase as a marker for immunoassays, the particles successfully con­ natural biological templates, as shown in Fig. 5 (E). The adsorption ef­
verted the motion change of particle to the colour signals in 2–3 s. All ficiency of lead ions has been greatly improved by the swarm of
experimental results have confirmed that the detection limit of this microrobot driven by rotate magnetic field, which was twice that of
method was well below the clinical threshold (2 ng/mL) with 99% static results. Compared with the mechanical stirring, the adsorption
confidence level, which is beneficial for monitoring the change of PCT efficiency increased 30%, and the adsorption capacity could reach
level in high-risk patients. Rapid detection of other biomarkers in the 245.1 mg/g, which was superior to the adsorbent based on MnO2 (Gong
blood can also be realized by changing the type of antibody in the Janus et al., 2021). In 2016, Vilela et al. reported that graphene oxide tubular
coating, as shown in Fig. 5 (B). microrobots removed and recovered heavy metal lead ions from sewage
under the action of hydrogen peroxide or external rotating magnetic
5.2. Magnetic micro/nanorobots for nucleic acid detection field, realizing the microrobot to capture, release, and recycle heavy
metal particles at specific locations (Vilela et al., 2016), as shown in
As a key step in biomedical and clinical diagnosis, the detection of Fig. 5 (F). The experimental results showed that the Gox microrobot
nucleic acids has attracted significant attention and has strict re­ could reduce the concentration of lead ions from 1 ppm to less than 0.4
quirements. In 2020, Pearlman et al. achieved high-gradient magnetic ppm within 10 min, and 80% of lead ions in sewage could be effectively
separation based on magnetic beads, steel wool, and external magnetic absorbed by the microrobot within 1 h. When the microrobot moved
field, and successfully extracted nucleic acid DNA from sputum and freely, the contact between microrobot and lead ion increased due to the
urine matrix. The extraction efficiency of the commercial kit was enhanced lead ion diffusion, and the decontamination efficiency
10–17% and 70–96%, respectively, while the extraction efficiency of increased from 7.7 ± 4.5% to 83.2 ± 1.0%. Increasing the number of
nucleic acid in sputum and urine was 10% and 90% using this method, microrobots could make the concentration of lead ion below 50 ppb, and
respectively, and the capture efficiency of magnetic beads in steel wool the capture efficiency increased from 83.2% to more than 95%. The
matrix could reach 100% (Pearlman et al., 2020). This method is not combination of magnetic micro/nanorobots, multi-functional nano­
only conducive to the magnetic purification of biomarkers, but also re­ particles, and composite materials provides the possibility to explore
duces external pollution. Early researchers proposed the concept of the novel adsorbents and construct multi-functional micro/nanorobots
biological detection system, which combined magnetic microsystem, integrating multiple adsorption and detection, exhibiting excellent po­
micro processing technology and microfluidic circuit to achieve specific tential for environmental governance and biosensors.
and selective detection of hybrid DNA, the magnetic capture of the 25
nucleotide biological targets. And the detection and analysis of 20.8 nM 5.4. Pathogenic microorganisms and biotoxins
nucleic acid solution have been realized in the chip and the
signal-to-noise ratio of 40.3 dB was obtained, reducing the complexity of Functionalized micro/nanorobots also have many applications in the
the biological detection process (Li et al., 2014). Recently, Trick et al. detection of pathogenic microorganisms (such as bacteria, viruses) and
separated virus particles from blood samples by using magnetic fluid toxins (Banerjee et al., 2015). In area of bacteriology, endotoxin refer to
technology. Under the action of external magnetic field, the magnetic lipopolysaccharide complexes related to the outer membranes of
beads automatically captured and purified nucleic acids and perform Gram-negative pathogens (Escherichia coli, Salmonella, Vibrio cholerae).
qPCR reactions, realizing the detection of 1000 HIV virus particles from In 2013, Wu et al. first proposed a method for rapid extraction, isolation
whole blood within 30 min (Trick et al., 2022). This has targeted to solve and detection of Pseudomonas aeruginosa endotoxin from human urine
the problems such as the inability to screen infection with higher samples using chitosan nanomagnetic membrane. The experimental
sensitivity, and the inability to quantify HIV RNA loads, breaking results showed that the sensitivity of CuFeO2@chitosan nanomagnetic
through the limitation of clinical trials only. However, this method has membrane was 250 times higher than that of Fe3O4@chitosan nano­
not been fully automated yet, it is expected to further shorten the magnetic membrane, and the lowest detection concentration was 30
detection time and simplify the workflow. mg/mL. Compared with the traditional matrix-assisted laser desorption
ionization mass spectrometry, the sensitivity of chitosan nanomagnetic
5.3. Magnetic micro/nanorobots for heavy metal ion detection membrane was 67 times higher (Gopal et al., 2013). In addition, the
team prepared graphene magnetic nanosheet decorated with chitosan
Excessive amounts of heavy metal ions in the environment are biosensors, which was combined magnetic nanoparticles with graphene
extremely harmful to all living beings and these heavy metals can materials and modified by chitosan. It was applied in rapid, sensitive,
accumulate in organisms either directly or indirectly through the food and low-cost detection of Pseudomonas aeruginosa and Staphylococcus
chain, causing various diseases and injuries. In 2017, Miao et al. aureus in water suspension and mouse blood samples. The graphene
demonstrated firstly a sensing strategy for simultaneous detection of magnetic nanosheet decorated with chitosan also has biocompatibility,
Ag+ and Hg+ using DNA-modified magnetic nanoparticles. C–C and T-T good robustness and simple determination process, which can realize
mismatches were used to generate metal-mediated base pairs in DNA the separation and pre-concentration of nanoprobe and bacterial cell
double chains, which could be strongly combined with Ag+ and Hg+, suspension under the action of external magnetic field (Abdelhamid and

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Wu, 2013). 6. Application of magnetic micro/nanorobots in the field of

Based on previous reports, Jurado-Sanchez et al. developed a kind of targeted delivery
ultra-fast sensors for detecting endotoxin in Escherichia coli, lipopoly­
saccharide in untreated urine and serum samples, which were modified Traditional drug delivery methods rely mainly on the humoral cir­
by graphene quantum dots and phenylboric acid. Graphene quantum dots culatory system. Magnetic micro/nanorobots, including micro/nano­
interacted with lipopolysaccharide, and phenylboric acid acted as lipo­ motors and various magnetic particles, have the potential to deliver or
polysaccharide specific recognition receptor (Jurado-Sanchez et al., autonomously navigate therapeutic drugs to focal lesions rapidly, which
2017). When glucose, galactose and fructose existed at the same time, not only improves their therapeutic effect, but also significantly reduces
the determination results were not interfered with matrix components, damage caused by the side effects of drugs on the human body. This
showing the highly selective screening capability. The Janus microrobot exciting alternative method of drug transportation (Luo et al., 2018)
sensor adopted a dual-mode driving method, providing reference for the offers an important and attractive platform for solving human health
autonomous detection of various toxins by micro/nanorobot in the problems.
future. In 2018, Escarpa et al. developed magnetic graphene/nick­
el/platinum nanoparticle micromotor. The outer graphene layer of 6.1. Targeted delivery of magnetic spiral micro/nanorobots
micromotor was used for adsorption, the inner platinum nanoparticle
played a catalytic role, and the middle magnetic layer was used to The unique characteristics of magnetic micro/nanorobots (Li et al.,
capture free aptamers by controlling the movement of micromotor 2017; Wu et al., 2015; Walker et al., 2015) facilitate the detection and
(Molinero-Fernandez et al., 2018), as shown in Fig. 5 (G). When this diagnosis of multidimensional and biological targets (Anderson et al.,
micromotor was used to determine aflatoxin B1, it showed that the 2019; Burrell et al., 2013). In 2018, Bozuyuk et al. reported a double
micromotor sensor had high sensitivity, accuracy and quantitative re­ helix micro/nanorobot that actively releases chemotherapeutic drugs
covery (104 ± 4%), and the detection limit was 0.70 ng/mL, which was under the action of magnetic force and light stimulation (Bozuyuk et al.,
much lower than the legal requirement of European Union (0.2 μg/mL). 2018). This microrobot can be degraded into non-toxic products under
Compared with conventional liquid chromatography and tandem mass certain conditions, which is an additional advantage for targeted de­
spectrometry, this biosensor overcome the disadvantages of livery, as shown in Fig. 6 (A). In 2020, Chen et al. systematically sum­
non-transferability, laborious and time-consuming. In the case of hay­ marised the idiographic advantages of magnetic micro/nanorobots in
cotoxin interference, it still demonstrated excellent selectivity, showing biomedicine with a focus on the major challenges associated with clin­
the great potential of micromotor as a new paradigm in biological ical applications (in vivo/vitro) (Koleoso et al., 2020). Magnetic
detection. micro/nanorobots with special structures enable the loading of various
In 2020, Zhang’s team developed a fluorescent magnetic spore drugs and different products, but dose delivery is limited by the effect of
microrobot sensing platform, which used the cooperation of natural adhesion in a fluid environment.
spores, magnetic nanoparticles, and functionalized carbon nanoparticles
to detect the toxin secreted by Clostridium difficile from clinical patient 6.2. Targeted delivery of magnetic particles
faeces (Yang et al., 2020b; Zhang et al., 2019). The microrobots driven
by magnetic field could be propelled continuously and effectively in The most important properties of magnetic particles in biomedicine
different media, which increased the diffusion and mass transfer of are their low toxicity, easy functionalization, biocompatibility, and
detected substance. The results showed that active motion has higher adjustability. They can also be attracted to a high magnetic flux density
detection efficiency than passive motion. The functional carbon spots under a magnetic field (Ito et al., 2005). As another method for medi­
could selectively bind to Clostridium difficile toxin, resulting in fluores­ ating drug delivery, magnetic particles can be functionalized to carry a
cence quenching. It could quickly be determined whether Clostridium load of effective drugs to target ligands (Wang and Gao, 2012; Wu et al.,
difficile existed by real-time observation of the fluorescence change in 2014). In 2020, Jahanban-Esfahlan et al. proposed magnetic natural
the biological environment. Magnetic micro/nanorobots provided the hydrogel beads (Jahanban-Esfahlan et al., 2020) that can be used as
improved analysis characteristic, sensitivity and selectivity compared to drug carriers for ibuprofen. Additionally, therapeutic drugs could be
traditional biosensing detection methods. At present, the application of encapsulated in the hydrogels to target HeLa cells, as shown in Fig. 6 (B).
micro/nanorobots in detection is still in the laboratory stage, and the As a promising tool for active targets, Juneja et al. synthesized niosome
research in practical applications has been seriously restricted by the (NIO) doped with iron oxide nanoparticles and fluorophores, which
complex detection environment. Meanwhile, the active sensing mode contained nonionic surfactants and other compounds (e.g., cholesterol
based on magnetic micro/nanorobots provides a new idea for re­ and lipids). Through the determination of the release kinetics and
searchers, as shown in Table 2, which is expected to further expand the cytotoxicity of the fluorophores, it was proved that NIO doped with
application of magnetic micro/nanorobots in different fields in the dyestuff has good encapsulation properties. When nanoparticles interact
future. with cells in vitro, nanocarriers are absorbed by a large number of cells
and this uptake can be enhanced by a magnetic field. As more efficient

Table 2
Applications of different types of micro/nanorobots in the detection field.
Types Targets Characterization way Detection effect Reference

magnetic spore-based bacterial toxins fluorescence microscopy detection finished within only 20 min Zhang et al. (2019)
microrobots
colloidal motors Hg ions inductively coupled plasma- removing efficiency up to ~90% with 40 min in the Ikram M. et al. (2021)
mass spectrometer contaminated water
microswimmer miRNA-141 and thrombin electrochemical detection capture trace disease markers in 30min, and detection Wang et al. (2022)
limitation down to 4.73 aM and 29.60 aM
Janus micromotor lipopolysaccharides or changes of fluorescence greatly enhanced mass transport, and increase the reaction Jurado-Sanchez et al.
endotoxins intensity rate between LPS-contaminated solution and micromotors (2017)
magneto-fluorescent Legionella pneumophila fluorescence microscopy and the capturing efficiency of up to ~50% of L.pneumophila cells, Martynenko IV et al.
microbeads DSM 7513 flow cytometry and the lowest cell concentration down to 100 CFU/mL (2019)
Magneto-aerotactic tumour cell (HCT116) immunohistology staining and 55% of MC-1 cells loaded drug-containing nanoliposomes Ouajdi Felfoul et al.
bacteria section analysis penetrate into hypoxic area of HCT116 colorectal xenografts (2016)

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X. Deng et al. Biosensors and Bioelectronics 222 (2023) 114960

Fig. 6. Targeted delivery of different magnetic

micro/nanorobots. (A) Light-triggered drug release
from biocompatible and biodegradable magnetic
chitosan microswimmers (Reproduced from ref
(Bozuyuk et al., 2018; Ceylan et al., 2019). with
permission of American Chemical Society, copyright
2018 and 2019). (B) Intelligent drug delivery system
based on magnetic nanoparticles for cancer therapy
(Reproduced from ref (Jahanban-Esfahlan et al.,
2020). With permission of Elsevier, copyright 2020).
(C) Targeted delivery of nanoliposomes to tumour
hypoxic regions by magneto-aerotactic bacteria
(Reproduced from ref (Felfoul et al., 2016). with
permission of Springer Nature, copyright 2016). (D)
Magnetic macrophage cell robot targeted therapy for
solid tumours (Reproduced from ref (Dai et al., 2021).
with permission of Wiley-VCH, copyright 2021). (E)
Real-time navigation, formation, and release of
porcine coronary arteries in vitro (Reproduced from
ref. (Wang et al., 2021). under the terms of the CC-BY
Creative Commons Attribution 4.0 International Li­
cense). (F) Microrobot for invitro fertilisations or
embryo transfer (Reproduced from ref (Koseki et al.,
2022). under the terms of the CC-BY Creative Com­
mons Attribution 4.0 International License).

and biocompatible drug delivery carriers, magnetic nanoparticles cause magnetic field to deliver drugs to the target location precisely, as shown
no damage to normal cells or tissues during the targeting process (Juneja in Fig. 6 (D). Under near-infrared stimulation, the anticancer drug DOX
and Roy, 2018). carried by the cell robots was released to kill a tumour (Dai et al., 2021).
These experiments proved the biological safety of cell robots, which are
6.3. Targeted delivery of magnetic biohybrid micro/nanorobots expected to be transformed into an important clinical drug delivery
platform and play a role in tumour-targeted therapy. Because the human
Propulsion based on a magnetic field is generally applied to magnetic environment is highly complex, most experiments are conducted outside
materials, which limits the applicability of magnetic micro/nanorobots. the body. Therefore, although research on magnetic micro/nanorobots
Therefore, many researchers have attempted to overcome this limitation has made some progress, there is still a long path to clinical application.
by combining magnetic micro/nanostructures coated with biocompat­
ible materials, micro/nanorobot devices, and natural microorganisms 6.4. Drug delivery of magnetic micro/nanorobot swarms
(Halder and Sun, 2019). In 2016, Felfoul et al. injected magnetotactic
bacteria, namely Magnetococcus marinus (MC-1), carrying drug-loaded Challenges have been encountered in drug dose loading, motion
nanoliposomes into tumour-bearing mice (Felfoul et al., 2016). Guided performance, and signal feedback for magnetic micro/nanorobots
by a magnetic field, the MC-1 bacteria reached the tumour area and (Ceylan et al., 2019; Wang et al., 2018; Xu et al., 2018). Researchers
penetrated colorectal cells (HCT116) into the hypoxic area of the have attempted to manipulate the delivery of drug doses to target areas
tumour, as shown in Fig. 6 (C). The results indicated that this type of effectively by using micro/nanorobot swarms. Recently, Li et al. re­
microorganism with a magnetic-air tendency can significantly improve ported a strategy for active intravascular delivery using magnetic Fe3O4
the delivery efficiency of drug nanocarriers to the hypoxic areas of tu­ nanoparticle microswarms guided by ultrasound Doppler imaging
mours. In 2021, Feng et al. proposed a magnetically controlled cell robot (Wang et al., 2021). A swarm experiment was conducted in the coronary
based on a macrophage drug carrier, which utilised the endocytosis of arteries of pigs, as shown in Fig. 6 (E). The research team used ultrasonic
macrophages to enrich Fe3O4 nanoparticles, DOX, indocyanine green, Doppler imaging equipment to track, navigate, and locate objects in real
etc. into cell interiors. The cell robots were driven by an external time. Under a rotating magnetic field, nanoparticles can be transformed

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into particle chains through their interactions. Additionally, it was For example, more flexible structures of micro/nanorobots, higher mo­
determined that periodic changes in the magnetic field or magnetic tion efficiency, more comprehensive functions, lower costs, and high-
gradient could alter the distances between particle chains to ensure that quality process development methods will significantly promote the
the particle swarm remained in a balanced state of dynamic stability. development of magnetic micro/nanorobots to unprecedented levels,
The experiment also proved that this switchable configuration was enhancing their applicability in the fields of biological detection and
conducive to the formation of a microswarm, navigation, and the release medical diagnosis. To this end, we must make further breakthroughs in
of nanoparticles. The combination of imaging technology with micro­ the following areas, as shown in Fig. 7.
robot swarms is beneficial for achieving targeted drug delivery and
other transport tasks in deep-tissue environments. Because the accurate (i) Innovatively design the functional structure of magnetic
control of motion and complex environments is difficult to achieve, joint micro/nanorobots. The advanced functional structure and charac­
efforts from various researchers are still required to conduct deeper teristic are conducive to the efficient swimming, capture, detection
research on the targeted delivery of micro/nanorobot swarms. and targeted treatment of magnetic micro/nanorobots in different
biological media or environments, avoiding the damage or destruc­
6.5. In vitro fertilisation using magnetic micro/nanorobots tion of biological tissues, organs or nervous system. In terms of
detection and targeted delivery, the multi-functional structure of
Relevant studies from the World Health Organisation have proven magnetic micro/nanorobots directly affects the adsorption effi­
that most male sperm cannot successfully reach the female egg (Mag­ ciency, sensing performance, drug loading dose, movement behav­
danz and Schmidt, 2014; Naser et al., 2021) as a result of the abnormal iour and release mechanism of micro/nanorobots to pollutants in
movement or morphology of sperm, weak sperm activity, few sperm, or practical operation and application. Currently, the effective multi-
high semen viscosity (Aziz et al., 2020; Rashid et al., 2020). Therefore, functional structures are still one of the constraints if magnetic
even with frequent sexual life, it may be difficult to succeed in the micro/nanorobots want to shuttle freely in the narrow areas such as
reproductive process (Naser et al., 2021). Current artificial insemination human capillaries and gastrointestinal tract and perform complex
methods have low success rates and high costs, leading to significant operations. This not only requires that the structure of micro/
stress for many couples (Naser et al., 2021; Singh et al., 2020). There­ nanorobots is deformable and their movement is sustainable, but
fore, scientists have attempted to solve this problem by developing also these swarm micro/nanorobots with high flexibility are easily
magnetic micro/nanorobots that are similar in size and behaviour to manipulated, even self-evolution.
sperm. Schmidt et al. introduced a microbiorobot composed of motile (ii) Explore the novel batch preparation process of magnetic
cells combined with magnetic microtubules propelled by flagella micro/nanorobots. The preparation process of common magnetic
(Magdanz et al., 2013). Under an external magnetic field, the remote micro/nanorobots is relatively mature, but the common problems
separation of microbiorobots can be realized, which is beneficial for are the complicated manufacturing process, tedious steps, and high-
guiding a single high-quality sperm cell to an oocyte for insemination. In cost. Magnetic micro/nanorobots based on rigid structures are
2016, Medina-Sánchez et al. manipulated an artificial micromotor to difficult to adapt to the living environment in practical applications.
capture, guide, and release single sperm cells actively on a microfluidic Therefore, the researchers need still to explore and learn from the
platform and successfully transported individual sperm cells into oo­ structure, composition, and surface characteristic of natural organ­
cytes (Medina-Sanchez et al., 2016). However, these processes were all isms or life composition (e.g., immune cells). Making full use of the
completed under simulated physiological conditions and it takes a long principle of bionic science and integrating cutting-edge
time to achieve actual oocyte fertilisation in a natural environment. In manufacturing technology try to construct intelligent micro/nano­
2020, the same group studied the capability of sperm-driven micro­ robots with high adaptability, biocompatibility and easily repeatable
motors to move in the fluid in the reproductive tracts of cows (Magdanz operation. Meanwhile, the new renewable, green, sustainable prep­
et al., 2016; Striggow et al., 2020). Recently, Koseki et al. proposed a aration process, technology and synthesis methods need to be
novel assisted reproductive system that utilises soft microrobots for developed and have no further modification to achieve low-cost
embryo transfer, as shown in Fig. 6 (F). This system has been verified in batch production of micro/nanorobots. In fact, one of the most
an obstetrical human model and can effectively control the implantation effective strategies is to know and learn from nature. The structure
of embryos in specific locations using a magnetic field, thereby and composition of life in nature are far more complex and
improving the rate of pregnancy (Koseki et al., 2022). To achieve the wonderful than we thought. It is necessary to gather the joint efforts
successful fusion of sperm cells and eggs, it is not only necessary to and innovation of researchers from different disciplines.
consider the structure, driving modes, materials, performance, and other (iii) Develop environmentally friendly smart nano-functional
factors of magnetic micro/nanorobots, but also their biocompatibility, materials. Using magnetic micro/nanorobots for biosensing, detec­
release mechanisms, and removal in a physiological environment (Aziz tion, disease diagnosis is still in infancy in practical clinical appli­
et al., 2020; Magdanz et al., 2017). The application of magnetic cations. The complicated and changeable microenvironment (e.g.,
micro/nanorobots in the biomedical field is very attractive and prom­ complex network, high surface area and volume ratio, acidity and
ising, and they should have a bright future. alkalinity) of biological and human body means that micro/nano­
robots also have high requirements on morphology, structure, size
7. Conclusions and outlook and material composition. First of all, the composed material of
micro/nanorobots must be non-toxic, and micro/nanorobots don’t
The development of magnetic micro/nanorobots will have signifi­ have an immune or chemical reactions with host creatures/cells. The
cant ramifications for protecting and improving human health. This loaded drugs won’t cause damage or strong side effects on non-
study focused on the progress of magnetic micro/nanorobots in terms of diseased organs or tissues of human body, and immune attack and
their driving modes, functions, and applications in the areas of biolog­ biological pollution effects should be avoided as far as possible in
ical detection and targeted delivery. Magnetic micro/nanorobots can biofluids. Secondly, micro/nanorobots must be stored easily or
achieve specific tasks such as rotation, capture, and release under a biodegradable, which can adapt or respond quickly when the phys­
magnetic field. An efficient drive mode and proper functional processing iological environments change rapidly. The best way of micro/
can assist micro/nanorobots in obtaining improved performance, which nanorobots is excreted through the excretory system or metabolism.
is helpful for expanding their range of application. The functional and Ideally, micro/nanorobots retained will cause interference or ob­
behavioural characteristics of natural microorganisms have not yet been stacles to the normal physiological function of human body, or these
fully developed and utilised, so this area is open for further exploration. micro/nanorobots can be spontaneously degraded without external

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X. Deng et al. Biosensors and Bioelectronics 222 (2023) 114960

Fig. 7. Schematic illustration of the perspective for the development of micro/nanorobots.

interference after the completion of detection, diagnosis, target, etc. are developed to realize real-time positioning, tracking, and explore
There is still a great space for the development and application of highly adaptive and sensitive driving and control strategies.
micro/nanorobots integrated with smart nano-functional materials (v) Multi-functional integration. The application of magnetic
(biomaterials, stimulating response materials, energy conversion micro/nanorobots have gradually turned from in vitro and chip to in
materials). The application of smart nanomaterials opens up new vivo. As a novel sensing platform, the multi-functional smart micro/
possibilities for designing and preparing the multi-functional intel­ nanorobots are expected to make adaptive response to the patients’
ligent response micro/nanorobots. internal environment, so as to better complete the tasks or higher
(iv) Innovate precise driving and control strategies. Although the commands of clinical diagnosis, detection, transmission and
researchers have explored the individual navigation, localization, removal. And the multi-functional micro/nanorobot system is ex­
imaging, and collective behaviour of magnetic micro/nanorobots, pected to achieve modularity, which can detect, analyse and image
and the relevant theories of the low Reynolds number motion, at the specified location. The different modules can not only interact
Brownian motion, and lattice Boltzmann method have been locally to complete different tasks, but also adapt to environmental
confirmed, it is still a huge challenge to realize the swarm commu­ change and cooperation. Through real-time tracking and observa­
nication, interaction, and multi-task cooperation similar to natural tion, the doctors can gain timely the feedback and grasp the internal
organisms in environment. The directional movement of magnetic pathological situation of human body from micro/nanorobots. At the
micro/nanorobots is seriously disturbed due to the molecular inter­ same time, the characterization equipment and methods involved in
action between fluids and the aggregation behaviour of micro/ the whole experiment process are also a problem to be solved. A
nanorobots in inhomogeneous medium (e.g., blood, cerebrospinal series of experimental processes such as the structural performance
fluid), and the speed and frequency of micro/nanorobots may change of micro/nanorobots, the sensitivity of detected substance, and the
sharply. At the same time, the existing imaging technology is not able targeted therapeutic effect depends on the special characteristic
to distinguish accurately micro/nanorobots, tissues, organs or lesion equipment or instruments. Therefore, it is necessary to further
site, relying on contrast agents. In order to promote precision navi­ improve the accuracy, sensitivity, stability, universality and opera­
gation, autonomous positioning and act on the lesion area, it is bility of the equipment. Only by integrating the multi-disciplinary
necessary to combine information technology, including machine knowledge of nanomanufacturing, assembly technology, microelec­
learning, image processing, deep learning, reinforcement learning tronic circuits, biotechnology and optoelectronics, can micro/nano­
and servo feedback control to further achieve the best motion robots break through the verification of concept and reach a new
behaviour (trajectory planning, obstacle avoidance) and improve the height. Therefore, there is still a long way to go for developing a
space resolution, which is from the micro-level to the submicron or highly sensitive and advanced micro/nanorobot sensing platform
nano-level. Meanwhile, the multi-mode imaging micro/nanorobots that are highly consistent, recyclable, safe and reliable. When the
shelf life or lifetime problem of micro/nanorobots are resolved,

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multi-functional intelligent micro/nanorobots will break through the Cacciola, F., Dugo, P., Mondello, L., 2017. Multidimensional liquid chromatography in
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CRediT authorship contribution statement Ceylan, H., Yasa, I.C., Yasa, O., Tabak, A.F., Giltinan, J., Sitti, M., 2019. 3D-Printed
biodegradable microswimmer for theranostic cargo delivery and release. ACS Nano
13 (3), 3353–3362.
Xue Deng: Conceptualization, Visualization, Methodology, Investi­ Cheang, U.K., Ali, J., Kim, H., Rogowski, L., Kim, M.J., 2017. On-surface locomotion of
gation, Writing-original draft. Yuan Su: Conceptualization, Writing- particle based microrobots using magnetically induced oscillation. Micromachines 8
review & draft. Minghao Xu: Methodology, Formal analysis. De Gong: (2).
Chen, X.-Z., Hoop, M., Mushtaq, F., Siringil, E., Hu, C., Nelson, B.J., Pane, S., 2017.
Writing-review & editing. Jun Cai: Method construction. Muhammad Recent developments in magnetically driven micro- and nanorobots. Appl. Mater.
Akhter: Writing-review & editing. Kehan Chen: Visualization. Shuting Today 9, 37–46.
Li: Conceptualization. Jingwen Pan: Visualization. Chao Gao: Inves­ Chen, X.-Z., Jang, B., Ahmed, D., Hu, C., De Marco, C., Hoop, M., Mushtaq, F., Nelson, B.
J., Pane, S., 2018. Small-scale machines driven by external power sources. Adv.
tigation. Daoliang Li: Writing-review & editing. Wenqiang Zhang: Mater. 30 (15).
Supervision, Funding acquisition, Writing-review & editing. Wentao Dai, Y.G., Bai, X., Jia, L.N., Sun, H.Y., Feng, Y.M., Wang, L.Y., Zhang, C.N., Chen, Y.Y.,
Xu: Conceptualization, Funding acquisition, Writing-review & editing. Ji, Y.M., Zhang, D.Y., Chen, H.W., Feng, L., 2021. Precise control of customized
macrophage cell robot for targeted therapy of solid tumors with minimal invasion.
Small 17 (41).
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