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.

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.

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.

Self-propelled nanomotor reconstructs tumor microenvironment through synergistic hypoxia alleviation and glycolysis inhibition for promoted anti-metastasis

Solid tumors always exhibit local hypoxia,resulting in the high metastasis and inertness to chemotherapy.Reconstruction of hypoxic tumor microenvironment(TME)is considered a potential therapy compared to directly killing tumor cells.However,the insufficient oxygen delivery to deep tumor and the confronting Warburg effect"compromise the efficacy of hypoxia alleviation.Herein,we construct a cascade enzyme-powered nanomotor(NM-si),which can simultaneously provide sufficient oxygen in deep tumor and inhibit the aerobic glycolysis to potentiate anti-metastasis in chemotherapy.Catalase(Cat)and glucose oxidase(GOx)are co-adsorbed on our previously reported CAuNCs@HA to form self-propelled nanomotor(NM),with hexokinase-2(HK-2)siRNA further condensed(NM-si).The persistent production of oxygen bubbles from the cascade enzymatic reaction propels NM-si to move forward autonomously and in a controllable direction along H_(2)O_(2) gradient towards deep tumor,with hypoxia successfully alleviated in the meantime.The autonomous movement also facilitates NM-si with lysosome escaping for efficient HK-2 knockdown to inhibit glycolysis.In vivo results demonstrated a promising anti-metastasis effect of commercially available albumin-bound paclitaxel(PTX@HSA)after pre-treated with NM-si for TME reconstruction.This cascade enzyme-powered nanomotor provides a potential prospect in reversing the hypoxic TME and metabolic pathway for reinforced anti-metastasis of chemotherapy.

Ultrasound-propelled Janus Au NR-mSiO_(2) nanomotor for NIR-II photoacoustic imaging guided sonodynamic-gas therapy of large tumors

Varieties of contrast agents have been developed for photoacoustic(PA)and ultrasound(US)imaging of cancers in vivo.However,access of traditional contrast agents into the sites of tumors has been principally through passive infiltration without any external force,preventing their deep penetration into the tissues of the tumors,and hindering the use of PA and US for deep tumor imaging.The concept of micro/nanomotors has been the focus of increasing attention as active theranostic agents due to their active movement in particular fluids,thereby conducting assigned tasks.Herein,US-propelled Janus mesoporous SiO_(2)partially coated gold nanorods(Au NR-mSiO_(2))were fabricated for deep tumor NIR-II PA imaging and synergistic sonodynamic-gas therapy.Following US irradiation,2,2-azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride(AIPH)loaded in mSiO_(2)(Au NR-mSiO_(2)/AIPH)generated N_(2)microbubbles with high efficiency to achieve nanomotor drive.Due to the deep penetration of US,the nanomotors exhibited a capability to travel deep within sites of tumors,providing enhanced PA/US imaging inside the tumors.Furthermore,the nanomotor based cancer therapy was demonstrated through synergistic N_(2)gas and sonodynamic therapy.The US-propelled nanomotors demonstrated a novel strategy for the simultaneous PA/US dual imaging deep within tumor tissues and precise therapy of large tumors.

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.

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.

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.

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.

Nanomotor-based adsorbent for blood Lead(II)removal in vitro and in pig models

Blood lead(Pb(II))removal is very important but challenging.The main difficulty of blood Pb(II)removal currently lies in the fact that blood Pb(II)is mainly complexed with hemoglobin(Hb)inside the red blood cells(RBCs).Traditional blood Pb(II)removers are mostly passive particles that do not have the motion ability,thus the efficiency of the contact between the adsorbent and the Pb(II)-contaminated Hb is relatively low.Herein,a kind of magnetic nanomotor adsorbent with movement ability under alternating magnetic field based on Fe3O4 nanoparticle modified with meso-2,3-dimercaptosuccinic acid(DMSA)was prepared and a blood Pb(II)removal strategy was further proposed.During the removal process,the nanomotor adsorbent can enter the RBCs,then the contact probability between the nanomotor adsorbent and the Pb(II)-contaminated Hb can be increased by the active movement of nanomotor.Through the strong coordination of functional groups in DMSA,the nanomotor adsorbent can adsorb Pb(II),and finally be separated from blood by permanent magnetic field.The in vivo extracorporeal blood circulation experiment verifies the ability of the adsorbent to remove blood Pb(II)in pig models,which may provide innovative ideas for blood heavy metal removal in the future.

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.

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.

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.

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.

Micro/nanomotor: A promising drug delivery system for cancer therapy

Micro/nanomotors(MNMs)are small-scale devices that can effectively convert various forms of energy into mechanical motion.Their controllable motility and good permeability have attracted the interest of researchers as promising drug carriers in cancer therapy.Compared with traditional formulations,micro/nanomotor drug delivery systems can greatly improve therapeutic efficiency and reduce the side effects of antitumor drugs.This review mainly discusses the advantages of micro/nanomotor drug delivery systems and the applications of MNMs propelled by exogenous,endogenous,and biohybrid power in cancer therapy.Finally,the main challenges of the applications of micro/nanomotor drug delivery systems,as well as future development trends and opportunities are discussed.

药物涂层球囊的研究进展

从抗增殖药物的优化、赋形剂的创新、包衣方法的改进以及智能药物涂层球囊(DCB)这几方面进行了综述。介绍了紫杉醇(PTX)、西罗莫司及其衍生物这两种常用抗增殖药物的优缺点和未来优化方向,阐述了碘普罗胺、聚氧化乙烯(PEO)、柠檬酸酯、角糖(KOS)等作为赋形剂的作用机理和未来应用前景。然后对微吸管法、浸渍包衣法、刷涂法、喷涂法等包衣方法进行了概述,阐释了各自的优缺点。随后对智能响应技术和DCB相结合的技术进行简述,介绍了超声响应型、光驱动型、气体驱动型、活性氧(ROS)响应型及微针(MN)涂层等智能DCB的作用原理和潜在应用。最后,在上述基础上对DCB存在的问题进行了分析,对DCB的未来发展方向进行了展望。