A Review on Artificial Micro/Nanomotors for Cancer-Targeted Delivery, Diagnosis, and Therapy

Micro/nanomotors have been extensively explored for efficient cancer diagnosis and therapy,as evidenced by significant breakthroughs in the design of micro/nanomotors-based intelligent and comprehensive biomedical platforms.Here,we demonstrate the recent advances of micro/nanomotors in the field of cancer-targeted delivery,diagnosis,and imaging-guided therapy,as well as the challenges and problems faced by micro/nanomotors in clinical applications.The outlook for the future development of micro/nanomotors toward clinical applications is also discussed.We hope to highlight these new advances in micro/nanomotors in the field of cancer diagnosis and therapy,with the ultimate goal of stimulating the successful exploration of intelligent micro/nanomotors for future clinical applications.

Recent Advances in One‑Dimensional Micro/Nanomotors:Fabrication,Propulsion and Application

Due to their tiny size,autonomous motion and functionalize modifications,micro/nanomotors have shown great potential for environmental remediation,biomedicine and micro/nano-engineering.One-dimensional(1D)micro/nanomotors combine the characteristics of anisotropy and large aspect ratio of 1D materials with the advantages of functionalization and autonomous motion of micro/nanomotors for revolutionary applications.In this review,we discuss current research progress on 1D micro/nanomotors,including the fabrication methods,driving mechanisms,and recent advances in environmental remediation and biomedical applications,as well as discuss current challenges and possible solutions.With continuous attention and innovation,the advancement of 1D micro/nanomotors will pave the way for the continued development of the micro/nanomotor field.

Visible light triggered exfoliation of COF micro/nanomotors for efficient photocatalysis

We report a new facile light-induced strategy to disperse micron-sized aggregated bulk covalent organic frameworks(COFs)into isolated COFs nanoparticles.This was achieved by a series of metal-coordinated COFs,namely COF-909-Cu,-Co or-Fe,where for the first time the diffusio-phoretic propulsion was utilized to design COF-based micro/nanomotors.The mechanism studies revealed that the metal ions decorated in the COF-909 backbone could promote the separation of electron and holes and trigger the production of sufficient ionic and reactive oxygen species under visible light irradiation.In this way,strong light-induced self-diffusiophoretic effect is achieved,resulting in good dispersion of COFs.Among them,COF-909-Fe showed the highest dispersion performance,along with a drastic decrease in particle size from 5μm to500 nm,within only 30 min light irradiation,which is inaccessible by using traditional magnetic stirring or ultrasonication methods.More importantly,benefiting from the outstanding dispersion efficiency,COF-909-Fe micro/nanomotors were demonstrated to be efficient in photocatalytic degradation of tetracycline,about 8 times faster than using traditional magnetic stirring method.This work opens up a new avenue to prepare isolated nanosized COFs in a high-fast,simple,and green manner.

Gas-propelled nanomotors alleviate colitis through the regulation of intestinal immunoenvironment-hematopexis-microbiota circuits

The progression of ulcerative colitis(UC)is associated with immunologic derangement,intestinal hemorrhage,and microbiota imbalance.While traditional medications mainly focus on mitigating inflammation,it remains challenging to address multiple symptoms.Here,a versatile gas-propelled nanomotor was constructed by mild fusion of post-ultrasonic CaO_(2) nanospheres with Cu_(2)O nanoblocks.The resulting CaO_(2)–Cu_(2)O possessed a desirable diameter(291.3 nm)and a uniform size distribution.It could be efficiently internalized by colonic epithelial cells and macrophages,scavenge intracellular reactive oxygen/nitrogen species,and alleviate immune reactions by pro-polarizing macrophages to the anti-inflammatory M2 phenotype.This nanomotor was found to penetrate through the mucus barrier and accumulate in the colitis mucosa due to the driving force of the generated oxygen bubbles.Rectal administration of CaO_(2)–Cu_(2)O could stanch the bleeding,repair the disrupted colonic epithelial layer,and reduce the inflammatory responses through its interaction with the genes relevant to blood coagulation,anti-oxidation,wound healing,and anti-inflammation.Impressively,it restored intestinal microbiota balance by elevating the proportions of beneficial bacteria(e.g.,Odoribacter and Bifidobacterium)and decreasing the abundances of harmful bacteria(e.g.,Prevotellaceae and Helicobacter).Our gas-driven CaO_(2)–Cu_(2)O offers a promising therapeutic platform for robust treatment of UC via the rectal route.

GSH-induced chemotaxis nanomotors for cancer treatment by ferroptosis strategy

Overexpression of glutathione(GSH) in tumor cells greatly inhibits the therapy effect of traditional ferroptosis inducers;thus,control of the GSH level is an important way to improve the efficacy of ferroptosis.Herein,a kind of nanomotor based on metal organic framework material NH_(2)-MIL-101 is constructed,in which polyethylene glycol(PEG) and glutathione hydrolase γ-glutamyltransferase(GGT) are asymmetrically modified to obtain mPEG@MIL-101@GGT nanomotors(PMG NMs).The nanomotor proposed in this article can be induced by overexpressing GSH in tumors to form chemotactic effects through the specific affinity between enzymes and substrates.Results indicate that the tail structure provided by PEG and the affinity between GGT and GSH can enable the stable chemotaxis behavior of nanomotors in a complex environment,thus enriching and penetrating deeply at the tumor site.In addition,after loading the ferroptosis inducer Erastin,the system shows a highly effective induction effect of tumor ferroptosis.Erastin in the system can effectively inhibit the synthesis of GSH,and PMG NMS can react with GSH through Fe^(3+)and GGT to promote GSH depletion.The produced Fe^(2+)can generate excessive reactive oxygen species through Fenton reaction,which further promotes the death of tumor cells.Meantime,the chemotaxis behavior of the nanomotors based on the endogenous biochemical reaction of GGT-catalyzed GSH hydrolysis can endow nanomotors with the enhanced delivery and penetration ability in tumors,thus collaboratively enhancing the ferroptosis effect.This strategy designed according to the physiological characteristics of tumors has good biosafety and treatment effect,providing new perspectives for micro/nanomotor and tumor treatment.

Near-infrared light-driven yolk@shell carbon@silica nanomotors for fuel-free triglyceride degradation

Yolk@shell mesoporous nanoparticles have received close attention due to their controllable structures and integrated functions.However,most yolk@shell nanosystems lack self-propulsion.Herein,yolk@spiky-shell structured carbon@silica nanomotors are fabricated with near-infrared(NIR)light self-thermophoretic propulsion as lipase nanocarriers for fuel-free triglyceride degradation.The light propulsion accelerates the accumulation of nanomotors on the droplet interface,and the efficient lipase loading further facilitates the rapid degradation of tributyrin droplets.By adjusting the yolk and spiky structure,the obtained semi-yolk@spiky-shell structured nanomotors exhibit the highest capacity of lipase(442 mg/g)and the highest light-driven diffusion coefficient(ca.55%increase under 2 W/cm^(2 )irradiation),thus improving the degradation efficiency of triglyceride(93.1%under NIR light vs.66.7%without NIR light within 20 min).This work paves the way to rationally design yolk@shell structured nanomotors for diverse applications.

Catalytic nanomotors： fabrication, mechanism, and applications

Catalytic nanomotors are nano-to-micrometer-sized actuators that carry an on-board catalyst and convert local chemical fuel in solution into mechanical work. The location of this catalyst as well as the geometry of the structure dictate the swimming behaviors exhibited. The nanomotors can occur naturally in organic molecules, combine natural and artificial parts to form hybrid nanomotors or be purely artificial. Fabrication techniques consist of template directed electroplating, lithography, physical vapor deposition, and other advanced growth methods. Various physical and chemical propulsion mechanisms have been proposed to explain the motion behaviors including diffusiophoresis, bubble propulsion, interracial tension gradients, and self-electrophoresis. The control and manipulation based upon external fields, catalytic alloys, and motion control through thermal modulation are discussed as well. Catalytic nanomotors represent an exciting technological challenge with the end goal being practical functional nanomachines that can perform a variety of tasks at the nanoscale.

Medical micro-and nanomotors in the body

Attributed to the miniaturized body size and active mobility,micro-and nanomotors(MNMs)have demonstrated tremendous potential for medical applications.However,from bench to bedside,massive efforts are needed to address critical issues,such as cost-effective fabrication,on-demand integration of multiple functions,biocompatibility,biodegradability,controlled propulsion and in vivo navigation.Herein,we summarize the advances of biomedical MNMs reported in the past two decades,with particular emphasis on the design,fabrication,propulsion,navigation,and the abilities of biological barriers penetration,biosensing,diagnosis,minimally invasive surgery and targeted cargo delivery.Future perspectives and challenges are discussed as well.This review can lay the foundation for the future direction of medical MNMs,pushing one step forward on the road to achieving practical theranostics using MNMs.

Near-infrared light-driven multifunctional metal ion(Cu^(2+))-loaded polydopamine nanomotors for therapeutic angiogenesis in critical limb ischemia

Most of the current nanomedicine-based treatments for critical limb ischemia(CLI)only aim at promoting angiogenesis,ignoring the negative influence on the therapeutic effects caused by the complex pathological micro-environment of ischemic tissue.Herein,near-infrared(NIR)light-driven metal ion(Cu^(2+))-loaded polydopamine(PDA)nanomotors(JMPN@Cu^(2+))is designed and prepared.Due to the good antioxidant and anti-inflammatory activities of PDA,JMPN@Cu^(2+)exhibits excellent biocompatibility and significantly improves the ischemic micro-environment.Additionally,based on superior photothermal conversion effect and jellyfish-like structure,the nanomotors are quickly propelled under NIR laser with low energy intensity to acquire the ability of movement and facilitate intracellular uptake of JMPN@Cu^(2+)by endothelial cells,resulting in the enhanced pro-angiogenic effect of Cu^(2+).Moreover,in vivo experimental findings show that JMPN@Cu^(2+)combined with NIR irradiation can successfully accelerate blood flow recovery and improve muscle repair.Taking these results together,this kind of nanomotor can promote angiogenesis along with ischemic micro-environment amelioration,holding great potential applications for the treatment of limb ischemia.

Chemical-NIR dual-powered CuS/Pt nanomotors for tumor hypoxia modulation,deep tumor penetration and augmented synergistic phototherapy

The complex tumor microenvironment(TME)with the characteristics of severe hypoxia,enriched hydro-gen peroxide(H_(2)O_(2))and dense nature significantly restricted the therapeutic efficacy of nanomedicine in cancer treatment.Synthetic micro/nanomotors have shown multiple versatility in modulating the abnor-mal TME and overcoming the limited penetration in solid tumor.Herein,we constructed a chemical-NIR dual-propelled nanomotor based on CuS/Pt Janus nanoparticles with IR820 encapsulation for hypoxia alle-viation,deep tumor penetration and augmented synergistic photodynamic(PDT)and photothermal ther-apy(PTT).The deposited Pt effectively catalyzed tumor endogenous H_(2)O_(2) into oxygen,which extremely relieved the tumor hypoxia state and allowed the chemical propulsion of nanomotors.Under NIR irra-diation,the Janus nanomotors exhibited more obvious movement via efficient photothermal conversion.Such autonomous motion significantly improved the tumoral accumulation of nanomotors and facilitated much deeper penetration inside tumor in vivo.In addition,enriched oxygen also promoted the genera-tion of reactive oxygen species(ROS)for augment of PDT,which achieved satisfied antitumor effect in combination with the PTT treatment.Therefore,this strategy based on CuS/Pt Janus nanomotors would provide an innovative dimension for considerable applications in effective cancer management.

Artificial nanomotors: Fabrication, locomotion characterization, motion manipulation, and biomedical applications

Artificial nanomotors are nanoscale machines capable of converting surrounding other energy into mechanical motion and thus entering the tissues and cells of organisms.They hold great potential to revolutionize the diagnosis and treatment of diseases by actively targeting the lesion location,though there are many new challenges that arise with decreasing the size to nanoscale.This review sum-marizes and comments on the state-of-the-art artificial nanomotors with ad-vantages and limitations.It starts with the fabrication methods,including common physical vapor deposition and colloidal chemistry methods,followed by the locomotion characterization and motion manipulation.Then,the in vitro and in vivo biomedical applications are introduced in detail.The challenges and future prospects are discussed at the end.

Designing bioactive micro-/nanomotors for engineered regeneration

Micro/nanoscale motors(MNMs)have been regarded as promising tools in the field of engineered regeneration due to unique property of autonomous motion.Herein,a review on the advancements of MNMs in the area of engineered regeneration is presented,covering aspects from their propulsion mechanisms to their frontiers in engineered regeneration,listing the revolutionary applications in biosensing,medical imaging,drug delivery and tissue engineering.Finally,challenges and future directions of MNMs are finally discussed on the basis of the achievements.

One-dimensional micro/nanomotors for biomedicine:delivery,sensing and surgery

The rapid development of artificial micro/nanomachines brings promising strategies to overcome challenges in biomedicine,including delivery,sensing and surgery.One-dimensional(1D)micro/nanomotors are one of the most attractive micro/nanomachines due to their high specific surface area,powerful impetus and weak rotation diffusion.In this review,different propulsion mechanisms and motion control strategies of 1D micro/nanomotors are summarized,and recent efforts towards their fabrication methods and biomedical applications are discussed.We envision the multidisciplinary research efforts in the field of 1D micro/nanomotors will pave their way to practical applications in bioimaging and biomedicine.

Recent progress on the design and fabrication of micromotors and their biomedical applications

The advancement in the micro-/nanofabrication techniques has greatly facilitated the development of micromotors.A variety of micromotors have been invented with powerful functions,which have attracted a broad range of interests from chemistry, physics,mechanics,biology and medicine.In this paper,we reviewed recent progress in micromotors and highlighted representative works.The mechanisms of micromotors by internal and external energy sources were described.We described general fabrication strategies of the popular micromotors (wire,tubular,helical and Janus)including bottom-up and top-down approaches.In the application section,we primarily focused on the biological applications,such as biological cargo delivery, biosensing and surgery.At last,we discussed the current challenges and provided future prospects.

An NIR-propelled janus nanomotor with enhanced ROS-scavenging,immunomodulating and biofilm-eradicating capacity for periodontitis treatment

Periodontitis is an inflammatory disease caused by bacterial biofilms,which leads to the destruction of periodontal tissue.Current treatments,such as mechanical cleaning and antibiotics,struggle to effectively address the persistent biofilms,inflammation,and tissue damage.A new approach involves developing a Janus nanomotor(J-CeM@Au)by coating cerium dioxide-doped mesoporous silica(CeM)with gold nanoparticles(AuNPs).This nanomotor exhibits thermophoretic motion when exposed to near-infrared(NIR)laser light due to the temperature gradient produced by the photothermal effects of asymmetrically distributed AuNPs.The NIR laser provides the energy for propulsion and activates the nanomotor's antibacterial properties,allowing it to penetrate biofilms and kill bacteria.Additionally,the nanomotor's ability to scavenge reactive oxygen species(ROS)can modulate the immune response and create a regenerative environment,promoting the healing of periodontal tissue.Overall,this multifunctional nanomotor offers a promising new approach for treating periodontitis by simultaneously addressing biofilm management and immune modulation with autonomous movement.

Chemotactic nanomotor for multimodal combined therapy of glioblastoma

Glioblastoma(GBM) is the most aggressive malignant brain tumor. Due to the infiltration and heterogeneity of GBM, the obstruction of the blood-brain barrier(BBB) and the unique immunosuppressive mechanism, it is hard to achieve significant effects of GBM treatment. Here, a kind of chemotactic nanomotor that loaded with glucose oxidase(GOx) and carboxylated cisplatin(Pt(IV)) prodrug on the L-arginine-derived polymer is proposed. The nanomotors are driven by catalysis of glucose decomposition and the positive chemotaxis towards the GBM microenvironment where inducible nitric oxide synthase and reactive oxygen species are highly expressed. This facilitates the BBB crossing and GBM targeting of the nanomotors. In addition, the released nitric oxide(NO) during propulsion as well as the loaded GOx and Pt(IV) can exert combined NO/starvation/chemotherapy. Meanwhile, it is able to induce and enhance the immune response through multiple pathways, thus better coping with the complexities of GBM treatment.

Bioinspired urease-powered micromotor as an active oral drug delivery carrier in stomach

Self-propelling micro-and nano-motors(MNMs)have been extensively investigated as an emerging oral drug delivery carrier for gastrointestinal(GI)tract diseases.However,the propulsion of current MNMs reported so far is mostly based on the redox reaction of metals(such as Zn and Mg)with severe propulsion gas generation,remaining non-degradable residue in the GI tract.Here,we develop a bioinspired enzyme-powered biopolymer micromotor mimicking the mucin penetrating behavior of Helicobacter pylori in the stomach.It converts urea to ammonia and the subsequent increase of pH induces local gel-sol transition of the mucin layer facilitating the penetration into the stomach tissue layer.The successful fabrication of micromotors is confirmed by high-resolution transmission electron microscopy,electron energy loss spectroscopy,dynamic light scattering analysis,zeta-potential analysis.In acidic condition,the immobilized urease can efficiently converted urea to ammonia,comparable with that of neutral condition because of the increase of surrounding pH during propulsion.After administration into the stomach,the micromotors show enhanced penetration and prolonged retention in the stomach for 24 h.Furthermore,histological analysis shows that the micromotors are cleared within 3 days without causing any toxicity in the GI tract.The enhanced penetration and retention of the micromotors as an active oral delivery carrier in the stomach would be successfully harnessed for the treatment of various GI tract diseases.

Light hybrid micro/nano-robots:From propulsion to functional signals

Untethered motile micro/nanorobots(MNRs)that can operate in hard-to-reach small space and perform noninvasive tasks in cellular level hold bright future in healthcare,nanomanufacturing,biosensing,and environmental remediation.Light,as a flexible encoding method with tunable freedom of intensity,wavelength,polarization,and propagation direction,endows unique spatialtemporal precision and dexterity to the manipulation of MNRs.Meanwhile,light has been extensively investigated as functional signals in bioimaging,phototherapy,as well as photoelectrochemical reactions.The hybridization of light and other actuation method ushers in novel MNRs with broadened design space,improved controllability,and advanced functionality.In this review,the fundamental mechanisms of light-driven MNRs will be revisited.On top of it,light hybrid systems,coupling with magnetic,electric,chemical,or ultrasound field,will be reviewed,with light for propulsion or as functional signal.The rational hybridization of multiple stimulus in MNRs not only promises simple combination of two driving forces,but more importantly,motivates rethinking of light-driven MNRs for unprecedented applications.

Amphiphilic AIEgen-polymer aggregates:Design,self-assembly and biomedical applications

Aggregation-induced emission(AIE)is a phenomenon in which fluorescence is enhanced rather than quenched upon molecular assembly.AIE fluorogens(AIEgens)are flexible,conjugated systems that are limited in their dynamics when assembled,which improves their fluorescent properties.This intriguing feature has been incorporated in many different molecular assemblies and has been extended to nanoparticles composed of amphiphilic polymer building blocks.The integration of the fascinating AIE design principle with versatile polymer chemistry opens up new frontiers to approach and solve intrinsic obstacles of conventional fluorescent materials in nanoscience,including the aggregation-caused quenching effect.Furthermore,this integration has drawn significant attention from the nanomedicine community,due to the additional advantages of nanoparticles comprising AIEgenic molecules,such as emission brightness and fluorescence stability.In this regard,a range of AIEgenic amphiphilic polymers have been developed,displaying enhanced emission in the self-assembly/aggregated state.AIEgenic assemblies are regarded as attractive nanomaterials with inherent fluorescence,which display promising features in a biomedical context,for instance in biosensing,cell/tissue imaging and tracking,as well as(photo)therapeutics.In this review,we describe recent strategies for the design and synthesis of novel types of AIEgenic amphiphilic polymers via facile approaches including direct conjugation to natural/synthetic polymers,polymerization,post-polymerization and supramolecular host−guest interactions.Their self-assembly behavior and biomedical potential will be discussed.

A Magnetocatalytic Propelled Cobalt-Platinum@Graphene Navigator for Enhanced Tumor Penetration and Theranostics

Complex biological environments and multiple physiological barriers significantly impede efficient accumulation and penetration of nanomaterials within tumor tissue for therapy.In situ energy conversion of nanomotors features autonomous movements and improves cancer treatment.However,one of the key challenges is to prepare nanomotors with an adequately small size,good biocompatibility,and precise positioning.Herein,we demonstrate a simple,ultrasmall,versatile,and real-time motion guidance strategy for magnetocatalytic CoPt@graphene navigators(MCGNs)that can enable highly efficient propulsion in the presence of H_(2)O_(2) or magnetic actuation.MCGNs act as highly diffusive delivery vehicles to promote tumor tissue targeting,and the amount of drug in the tumor was three times than without navigation.By engaging movements powered through in situ energy conversion,MCGNs gain considerable propulsion to penetrate a cell’s membrane and enhance intracellular delivery.