Micro/nanomotor development towards enhanced cancer therapy

Abstract

Cancer remains a leading global life-threatening disease, with traditional cancer therapies hindered by inefficient drug delivery and the complex tumor microenvironment. Micro/nanomotors—nanomaterials capable of converting chemical, physical, or biological energy into autonomous mechanical motion—emerge as a transformative tool for precision oncology. By overcoming the limitations of passive drug carriers, these motors enable active penetration of tumor barriers, targeted cargo delivery, and spatiotemporally controlled therapy, offering unprecedented opportunities to enhance treatment efficacy and reduce systemic toxicity. This review synthesizes the latest advancements in micro/nanomotors for cancer therapy, taking their diverse driving mechanisms as the central axis to explore their therapeutic potential. The article systematically categorizes these motors into chemical-driven (e.g., bubbles, self-electrophoresis, and enzymes), physical-driven (e.g., magnetic, ultrasonic, and light), multifield-coupled, and bio-hybrid systems. For each category, we elaborate on design principles, energy-conversion mechanisms, cancer-specific applications (e.g., targeted delivery, combinatorial therapy, and immune activation), and technical advantages, illustrating how different driving modalities address unique challenges in tumor microenvironments. Future progress requires interdisciplinary efforts to bridge experimental design with practical applications, aiming to transform these micro/nanomotors into effective tools for precise cancer therapy.

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1. Introduction

Cancer, as a major disease threatening global public health, faces treatment challenges due to the invasiveness, heterogeneity, and multidrug resistance of tumor cells, as well as the passive adaptation of existing treatment systems to the complex barriers of the tumor microenvironment. Only about 0.7% of nanodrugs in traditional drug delivery systems can reach solid tumors.¹ The ability to penetrate the extracellular matrix (ECM) of tumor cells to exert their effects is even rarer. This inefficiency is essentially due to the rapid clearance of mononuclear phagocytes in the circulatory system, coupled with the physical barrier composed of high interstitial fluid pressure, abnormal vascular structure, and dense matrix fibers in the tumor microenvironment.² Passive targeting strategies (such as the EPR effect) can only achieve superficial drug retention, leading to the clinical dilemma of “significant tumor surface killing but internal residual recurrence” in solid tumor treatment.

In recent years, in addition to traditional chemotherapy, immunotherapy has emerged as a new paradigm for cancer treatment. Immunotherapy combats cancer by activating the body's immune defense mechanisms. For example, it relieves the tumor-induced suppression of T cells by blocking immune checkpoints, restores the killing function of T cells to induce tumor cell apoptosis; alternatively, CAR-T cell therapy genetically engineers T cells to express chimeric antigen receptors (CARs), which specifically recognize tumor antigens and directly kill tumors by releasing perforins and granzymes.³ Nanoparticles can directly modify immune checkpoints on cancer cells or immune cells, induce innate and adaptive immune responses, and have thus become a versatile platform for inducing systemic anti-tumor immunity and enhancing the anti-cancer efficacy of traditional immunotherapies. Various types of nanomedicines, such as mesoporous silica nanoparticles,⁴ liposomes,⁵ micelles,⁶ polymeric nanoparticles,⁷ and gold nanoparticles,⁸ have been developed and fabricated for cancer immunotherapy. However, the delivery process of these nanomedicines also faces microenvironmental obstacles, making it difficult to achieve the desired immunotherapeutic effect. For instance, due to the hindrance of tumor interstitial fluid pressure (30–130 mmHg),⁹ anti-PD-L1 nanobodies (e.g., PEGylated liposomes) can only accumulate at the tumor edge, resulting in uneven spatial distribution within the entire tumor tissue and insufficient activation of T cells in deep tumors.¹⁰ CAR-T cell therapy has shown good efficacy in treating various hematological malignancies. Nevertheless, its efficacy in solid tumors has proven to be limited,^11,12 mainly because the tumor-associated extracellular matrix (ECM) creates a stubborn barrier for cytotoxic CAR-T cells that are supposed to kill cancer cells. Within tumors, the ECM undergoes significant remodeling, characterized by changes in its composition and covalent cross-linking of components, leading to increased stiffness and altered mechanical properties.^13,14 This remodeling not only helps create an immunosuppressive microenvironment but also forms a solid stromal barrier that hinders the delivery of nanomedicines and prevents the activation of effective anti-tumor immune responses. Therefore, in the face of the physical barriers posed by interstitial fluid pressure and the dense extracellular matrix (ECM) in the tumor microenvironment, the penetration efficiency of traditional passively delivered nanomedicines in solid tumors is significantly limited. There is an urgent need to develop nanomedicines with active motility to penetrate deep into tumors. These nanomedicines convert energy into motion, greatly enhancing displacement efficiency compared to Brownian motion. Active transport carriers can effectively deliver drugs to deep tumor regions by overcoming interstitial fluid pressure and matrix resistance. In the highly viscous tumor microenvironment, they maintain directional movement, avoiding being washed away by interstitial fluid convection. Moreover, in response to specific signals such as pH and metabolite concentrations in the microenvironment, they can dynamically adjust their motion patterns, enabling an intelligent regulatory process of obstacle recognition, penetration, and drug release. The key requirement for this active transport capability is to break through the concentration-dependent limitations of passive delivery and provide an innovative approach to address the delivery bottlenecks of traditional and emerging therapies, thereby improving cancer treatment outcomes.

Since Feynman envisioned manipulating matter at the atomic and molecular levels in his speech There's Plenty of Room at the Bottom in 1959, nanotechnology has undergone significant development. Micro/nanomotors can convert surrounding energy into mechanical motion, thereby achieving self-propulsion and breaking the constraints of irregular Brownian motion and low Reynolds numbers on the motion of micro/nano scale objects.¹⁵ Taking paramecium as an example, it achieves efficient propulsion through the coordinated swinging of about 4000 cilia. This movement mechanism relies on the ATP hydrolysis drive of dynein in the microtubule structure, forming a paddle-like movement mode, which drives paramecium to swim at a speed of 2–3 times its body length per second.¹⁶ Inspired by this, the research teams developed biomimetic micro/nanomotors that simulate the principle of cilia movement, converting chemical energy, light energy, or electromagnetic field energy into controllable mechanical motion. In 2004, Sen's team's research on catalyzing the autonomous movement of platinum nanomotors marked a groundbreaking achievement in the field of autonomous micro/nanomotors.¹⁷ In 2012, the PAPBA/Ni/Pt micro rocket developed by Wang et al. proposed a targeted separation strategy for nanomotors based on “built-in” recognition ability. The monosaccharide recognition ability of the outer PAPBA polymer layer combined with the catalytic function of the inner platinum layer achieved instant binding and transportation of target sugars, opening up the biomedical application research in the field of nanomotors for the first time.¹⁸ In 2018, micro/nano motors began to be applied in tumor treatment. A Janus mesoporous silica nanomotor with near-infrared (NIR) light power was designed to actively search for cancer cells.¹⁹ In 2019, a urease driven nanomotor based on mesoporous silica nanoparticles was designed to target bladder cancer cells in the form of 3D spheres.²⁰ In 2023, Zhang et al. synthesized N-doped jellyfish-like mesoporous carbon nanomotors (Cu JMCNs), combining single atom catalysis with nanomotor self-propulsion. By utilizing the jellyfish-like structure and the photothermal properties of carbon, self-thermal swimming motion was achieved, significantly enhancing tumor penetration ability and providing new design ideas for biomimetic nanomotors in the field of cancer treatment.²¹ In 2025, Hest et al. developed a mannose based nanomotor (c-CLEnM) and found for the first time that surface mannose polymer modification has a synergistic enhancement effect on the targeting and motion performance of nanomotors. This modification reduces the interference of surrounding ions on motion, providing a new strategy to solve the problem of decreased motion efficiency of traditional nanomotors in complex physiological environments of tumor tissue lighting.²² These research studies mark the evolution of the micro/nanomotor driving mechanism from a single chemical fuel to intelligent response and biocompatibility, providing key technical support for the construction of a precise tumor treatment system.

In recent years, significant progress has been made in the field of micro/nanomotors. Professor Tu's team systematically reviewed the reaction mechanisms of chemical micro/nanomotors,²³ while Cai and his colleagues categorized and summarized the driving mechanisms of one-dimensional motors.²⁴ Numerous studies have conducted in-depth explorations focusing on single-field regulation strategies, such as chemical,²³ magnetic,²⁵ and light/wave-driven mechanisms.²⁶ With the integration of interdisciplinary research, studies on composite driving systems—including chemical–physical multi-field coupling and biohybrid systems—have gradually emerged as new developmental directions. Their application value in biomedical fields such as drug delivery,^27,28 gastrointestinal diseases,²⁹ biological barrier overcoming, and in vivo imaging³⁰ has been gradually revealed. Notably, regarding the complex barriers unique to the tumor microenvironment in cancer therapy—such as high interstitial fluid pressure and stromal fibrosis—the mechanisms and application strategies of micro/nanomotors still require further integration with the latest research findings. Building upon previous studies, this review focuses on the cutting-edge advancements in various driving strategies, highlights the core challenge of tumor microenvironment penetration, and summarizes the latest breakthroughs of micro/nanomotors in breaking through physiological barriers and optimizing cancer treatment. It aims to provide a comprehensive reference for promoting academic development and clinical translation in this field.

This article takes various driving modes of micro/nanomotors as the axis (Scheme 1) and introduces their applications in tumor therapy, especially in the research progress of tumor targeted delivery, drug release regulation, immune activation, and integrated diagnosis and treatment. Finally, we summarized the key limitations faced by micro/nano motors in clinical translation, including insufficient precision in motion control, limited long-range transport capabilities, and deficiencies in intelligent response to complex microenvironments. We also looked forward to the prospects and future development directions of interdisciplinary research that integrates tumor microenvironment analysis with artificial intelligence algorithms to promote micro/nano motors from experiments to precise clinical treatment.

Scheme 1 Schematic illustration of the development of micro/nanomotors for cancer therapy: (i) chemical-driven (bubbles, self-electrophoresis, and enzymes); (ii) physical-driven (magnetism, ultrasound, and light); (iii) multifield coupling-driven (chemical energy and light energy); and (iv) bio-hybrid-driven (bacteria, cell membranes, and sperm).

2. Chemical driven micro/nanomotors

Cancer treatment faces challenges such as the complex tumor microenvironment, low drug delivery efficiency, and multidrug resistance. Traditional passive targeting strategies are difficult to break through the physiological barriers of tumors and achieve precise treatment. Chemical driven micro/nanomotors, as intelligent nanocarriers, break through Brownian motion limitations through autonomous movement and exhibit unique advantages in the tumor microenvironment: they catalyze the decomposition of endogenous tumor fuels (such as H₂O₂ and glucose) or exogenous added fuels (such as NO and H₂S) to generate bubble recoil or self-electrophoresis effects to drive motion. Among them, enzyme drive converts non-toxic or biocompatible fuels into mechanical force through enzymatic reactions,³¹ the bubble recoil mechanism provides propulsion through gas products,³² and self-electrophoresis drive induces local electric field propulsion through ion concentration gradients generated by chemical reactions.³² This multimodal driving characteristic not only enhances tumor penetration depth, but also enables precise drug release through the design of fuel responsive shells, synergistic photothermal/chemotherapy and other multimodal treatments. The diversity of chemical driving mechanisms provides an innovative path for constructing intelligent responsive nano platforms and lays a theoretical foundation for developing efficient and low toxicity anti-tumor strategies.

2.1. Bubble driven micro/nanomotors

Pulse propulsion for bubble growth and fluid dynamic jet propulsion for bubble rupture have become some of the most attractive methods for driving micro/nanomotors due to their high efficiency, fast movement speed, and low energy consumption. Bubble drive is also the most common type of chemical drive for nanomotors.^33–36 The essence of bubble driving is that one side of the micro/nanomotor undergoes a chemical reaction with the fuel solution, producing continuous bubbles. The reaction force generated by the release of bubbles on the motor drives the motor to move. Compared with traditional self-electrophoretic micro/nanomotors, bubble propulsion micro/nanomotors typically generate much higher speeds^16,17 and their efficiency can be further improved by utilizing the impact of strong jets.^36,37 Compared with motors driven by external fields, bubble propulsion motors can move on their own without any additional energy input.³⁸ Traditional bubble propulsion micro/nanomotors include tubular motors with catalytic surfaces manufactured in their inner chambers³⁹ and spherical Janus motors covered with hemispherical catalytic layers on their outer surfaces.⁴⁰ In recent years, various morphologies of micro/nanomotors such as bowl shaped⁴¹ and cap shaped have gradually been developed.

The micro/nanomotor fueled by H₂O₂ is currently the most reported bubble driven motor. In this type of particle, H₂O₂ is decomposed into O₂ in the presence of catalysts such as metal Pt, catalase, and peroxidase, and the asymmetric release of bubbles generates recoil to propel the movement. Its development process can be traced back to the platinum nanocapsules developed by He's team in 2013, which generated oxygen bubbles through platinum catalyzed H₂O₂, laying the foundation for subsequent research.⁴² In 2017, Tu et al. first proposed a biodegradable bowl shaped PEG-b-PCL/PEG-b-PS hybrid cellular nanomotor, which generates oxygen bubbles by catalyzing the decomposition of H₂O₂ with platinum nanoparticles.⁴¹ This design innovatively combines platinum catalytic activity with degradable polymers to achieve controlled release of doxorubicin (Dox) through lysosomal degradation in tumor cells. This work lays the foundation for subsequent research, but the structural stability in vivo still needs to be verified. On this basis, in 2021, Díez et al. developed a snowman shaped Janus Pt mesoporous silica nanomotor (Fig. 1a),⁴³ which is driven by the asymmetric distribution of platinum nano dendrites and mesoporous silica in a low concentration H₂O₂ environment. This design utilizes glutathione responsive release of drugs, solving the problem of how to accurately release drugs after reaching the tumor and deepening the accuracy of treatment. However, it has been found that the adsorption of blood components leads to a decrease in the speed of micro/nanomotor movement, making it difficult for drugs to penetrate tumor tissues, and the impact of fluctuations in H₂O₂ concentration in the tumor microenvironment on driving force still needs further research. In 2024, Wang et al. developed a cap shaped mesoporous organic silicon platinum Janus nanomotor (Fig. 1b) to address the challenge of tumor penetration.⁴⁴ This structure achieves charge reversal by breaking the β-carboxamide bond in acidic environment, and the surface potential changes from −25 mV to +30 mV, significantly enhancing the penetration ability of tumor tissue. The experiment showed that the nanomotor achieved a speed of 34.3 μm s⁻¹ at a concentration of 5% H₂O₂, and released Dox in response to glutathione, increasing the tumor inhibition rate to 85%. This design combines the charge reversal mechanism with bubble driving for the first time, providing a new approach to solving the diffusion bottleneck of nanoparticles in tumor stroma.

Fig. 1 Applications of bubble-propelled micro/nanomotors in cancer therapy. (A) Propulsion mechanism of Janus-Pt mesoporous silica nanomotors for precise drug release. Reproduced with permission from the ref. 43. Copyright 2017, Wiley-VCH. (B) Mesoporous organosilica–platinum Janus nanomotors integrating charge reversal mechanism with bubble-driven propulsion. Reproduced with permission from ref. 44. Copyright 2024, Elsevier. (C) SO₂ gas-driven gold–silver hollow nanotriangle nanomotors. Reproduced with permission from the ref. 46. Copyright 2020, Elsevier. (D) Hollow copper sulfide nanomotors loaded with gas signaling molecule donor NOSH for controllable release of H₂S/NO. Reproduced with permission from ref. 47. Copyright 2025, Elsevier.

In addition to the classic catalytic decomposition of H₂O₂, many other materials and chemical fuels are also used to generate bubbles and drive motors. The zero waste loaded heparin/folate/L-arginine (HFLA-Dox) NO driven nanomotor designed by Shen's team in 2021 utilizes nitric oxide gas to destroy tumor blood vessels and enhance chemotherapy drug penetration.⁴⁵ Li et al. has designed a gold silver hollow nano triangular nanorobot (Fig. 1c).⁴⁶ The triangular carrier is easier to enter cells than the ordinary spherical carrier. In the experiment, the fluorescence intensity was analyzed to be about 1.3 times that of the ordinary spherical carrier. By using the acidic conditions inside tumor cells to induce the on-demand release of sulfur dioxide gas from sulfur dioxide prodrugs, the nanorobot can move and the gas can diffuse inside the tumor cells, achieving the treatment of deep tumors. Subsequently, researchers made further breakthroughs and developed programmable NIR triggered nanomotors.⁴⁷ The motor is combined with hollow copper sulfide nanoparticles loaded with gas signal molecule donor NOSH, which can release H₂S/NO under 808 nm laser irradiation in a controllable manner, and maintain a local temperature below 45 °C through photothermal effect (conversion efficiency of 27.8%) (Fig. 1d). The experiment showed that the design realized the triple synergistic treatment of “photothermal ablation-gas sensitization-immune activation” in the 4T1 breast cancer model, the apoptosis rate of tumor cells reached 79%, and the immune microenvironment was reshaped through M1 macrophage polarization and CTLs infiltration. This study is the first to combine gas signaling molecules with photothermal therapy, providing a new strategy for the treatment of hypoxic tumors.

These studies indicate that micro/nanomotors propelled by bubbles have great potential in tumor targeted delivery, drug release regulation, and immune activation through morphology optimization, multi field collaborative driving and intelligent response design. From early single catalytic drive to multimodal synergistic therapy, from in vitro experiments to in vivo applications, research has gradually solved key problems such as insufficient driving force, difficulty in tumor penetration, and immune escape. Future research needs to further address challenges such as stability, biocompatibility, and clinical translation in living environments, and promote the transition of this technology from laboratory to clinical applications.

2.2. Self-electrophoretic driven micro/nanomotors

The driving force of the micro/nanomotor driven by bubbles depends on the local bubble generation efficiency, which is easily affected by factors such as diffusion resistance and viscosity changes in complex biological fluid environments, resulting in limited controllability of the motion trajectory and deep tissue penetration efficiency. In recent years, the proposal of the self-electrophoresis driving mechanism has provided new ideas for breaking through this limitation. Electrophoresis is a physical phenomenon that describes the directional motion of charged particles in the presence of an external electric field. The mechanism of self-electrophoresis is similar to that of electrophoresis, but the difference is that it describes the transport of charged particles driven by self-generated electric fields. This mechanism generates ion concentration gradients and local electric fields in situ through asymmetric catalytic reactions on the surface of nanomotors, driving particles to move autonomously without relying on external environmental signals. This fully autonomous driving mode significantly enhances the adaptability of nanomotors in complex physiological environments. The core of self-electrophoresis driving lies in the coupling of local electrochemical reactions triggered by catalytic reactions with electric fields. For a typical self-electrophoretic motor (Fig. 2a),⁴⁸ a portion of its surface contains chemically active materials that release ions, which are consumed in other parts of the particle surface, resulting in zero total ion current entering or leaving the particle surface at steady state. These processes typically occur at different ends of colloidal motors (such as the two opposing caps of Janus microspheres, the two ends of conductive carbon fibers, or the two segments of microrods). The resulting ion distribution generates an electric field that points from the region of excess cations to the region of depleted cations. When coupled with colloidal particles with surface charges (usually negative charges), this self-generated electric field moves the particles through electrophoresis, hence it is called self-electrophoresis. For example, in H₂O₂ solution, the thicker region of Pt film acts as the cathode for reduction reaction (H₂O₂ + 2H⁺ + 2e⁻ → 2H₂O), while the thinner region acts as the anode to promote oxidation reaction (H₂O₂ → O₂ + 2H⁺ + 2e⁻), thus forming a self-driven electric field on the particle surface. This electric driving mechanism enables the micro/nanomotor to maintain stable motion even under high ion intensity, breaking through the limitations of traditional diffusion swimming.

Fig. 2 Applications of self-electrophoresis-driven micro/nanomotors in cancer therapy. (A) Self-electrophoretic motors release ions at one side (“source”) and consume ions at the other side (“sink”), such that the overall ionic strength does not increase. Reproduced with permission from the ref. 48. Copyright 2022, Wiley. (B) The self-electrophoretic driving mechanism of Janus particles is surface asymmetry catalyzing chemical reactions. Reproduced with permission from ref. 49. Copyright 2018, American Chemical Society. (C) Self-electrophoretic Au–Zn nanotube motors generate a mechanically activated immune response. Reproduced with permission from the ref. 50. Copyright 2022, Wiley. (D) Ag–Pt self-electrophoretic motors enable chemical signaling between nanomotors. Reproduced with permission from ref. 51. Copyright 2017, Wiley. (E) The Au/Pt interfacial synergistic catalysis of glucose by Au/Pt “egg-nest” nanomotors. Reproduced with permission from ref. 52. Copyright 2021, Wiley.

Schatz et al. revealed the driving mechanism of Janus particles from both theoretical and mechanistic perspectives, proposing that the self-diffusion electrophoresis effect induced by surface asymmetric catalysis is the driving core. These nanoparticles are partially covered with catalysts on their surfaces and can react with fuel molecules in the solution to achieve self-propelled motion based on the concentration gradient generated by surface reactions (Fig. 2b).⁴⁹ Its chemotaxis originates from the active coupling of particle orientation and chemical gradient. When particles are in a fuel concentration gradient, they will adjust their movement direction and move towards the fuel source based on their surface properties and chemical reactions. This study provides a theoretical framework for understanding the driving mechanism of nanoparticles and key guidance for subsequent design.

The research on nanomotors driven by self-electrophoresis in the field of cancer treatment is showing a trend towards intelligent and precise development from a single function. Early research focused on mechanically activating immune responses, such as the Au–Zn nanotube motor (Fig. 2c) designed by Xie et al.,⁵⁰ which generates local mechanical force through water drive, activates Piezo1 mechanosensitive channels on the surface of T cells, triggers Ca²⁺ influx, and achieves targeted activation of T cells. This mechanical activation strategy avoids the systemic immune storm risk caused by traditional cytokines and provides a new local regulatory approach for tumor immunotherapy. As research deepens, the introduction of chemical communication mechanisms significantly enhances the intelligent collaboration capability of nanomotors. The PS/Ni/Au/Ag–SiO₂/Pt dual motor system constructed by Chen et al.⁵¹ achieved chemical signal transmission between nanomotors through the synergistic catalytic effect of Ag⁺ release and Pt surface, increasing the motion speed of the receiving motor by more than three times (Fig. 2d). This dynamic regulation mechanism lays the foundation for designing multimodal collaborative cancer treatment systems, such as constructing an activation responsive nanofleet to achieve spatiotemporal coordination of drug delivery and immune activation in the tumor microenvironment. The latest progress has shifted towards autonomous systems driven by metabolic fuels. Kwon et al. developed an Au/Pt “egg nest” nanomotor (Fig. 2e), which was prepared by dynamic casting method, with Au nanocrystals located at the bottom of the Pt dendritic network.⁵² Its self-electrophoresis mechanism is based on glucose oxidation reaction, and the Au/Pt interface synergistically catalyzes the generation of oxygen from glucose, forming a concentration gradient to drive movement. By utilizing the O₂ gradient generated by glucose oxidation to drive movement, an efficient propulsion of 20.4 μm s⁻¹ was achieved in a simulated physiological environment. Its unique Janus structure not only enhances drug loading capacity, but also increases the frequency of membrane interactions with tumor cells through continuous movement, resulting in a 40% increase in cell uptake efficiency. This autonomous system based on endogenous fuels solves the problem of low efficiency of traditional nanocarriers in complex biological fluids. This series of studies reveals three major development trends of self-electrophoretic micro/nanomotors in cancer treatment: evolving from single mechanical stimulation to chemical mechanical synergistic regulation, upgrading from static drug loading to dynamic autonomous delivery, and integrating from single treatment mode to multimodal treatment.

However, the current research on the driving mechanism of self-electrophoresis still faces multiple challenges. Firstly, the nanoscale regulation of catalytic surfaces requires atomic level precision to optimize the electric field distribution. In 2020, Guan et al.⁵³ prepared a large strawberry shaped structure PS@PDA Eccentric structure PS with core–shell hemisphere composition, dense island shaped Pt nanoparticles covering the surface, and a large number of nano pits PS@PDA@Pt nanomotors (PEMNMs), driven by ion diffusion electrophoresis triggered by the decomposition of H₂O₂ by Pt nanoparticles at low H₂O₂ concentrations, attempted to increase the efficiency of self-electrophoresis by three times through the design of nano grooves on the surface of the platinum shell. However, the stability of this structural regulation in the living environment still needs to be verified. Secondly, interference from blood components and pH fluctuations can easily lead to electrochemical reaction instability in the complex tumor microenvironment. From the study by Chen et al. in 2022,⁵⁴ they found that the surface plasmon resonance (LSPR) properties of metal nanoparticles (such as gold and silver) are affected by protein crowns, such as bovine serum albumin (BSA) adsorbed on the surface of gold nanorods, resulting in a decrease in their photothermal conversion efficiency and a decrease in the movement speed of self-electrophoretic nanomotors. Therefore, future research needs to break through the contradiction between atomic level precision regulation and biocompatibility at the material design level. While maintaining the stability of electrochemical reactions, it should be endowed with the ability to make autonomous decisions to avoid biological barriers. This will open up new paths for the clinical translation of self-electrophoresis driven mechanisms in precision cancer treatment.

2.3. Enzyme driven micro/nanomotors

Considering the prerequisite for biocompatibility in in vivo therapy, it is necessary to explore biocompatibility design that can be driven in biological systems without side effects. Therefore, enzymes that perform energy conversion in biological systems based on existing fuel sources and do not require external power sources are good candidates for addressing these issues.⁵⁵ Therefore, many enzyme powered micro/nanomotors have been developed, based on enzymes such as catalase, urease, glucoamylase, lipase, etc.^56,57 Enzyme powered micro/nanomotors convert non-toxic or biocompatible fuels into mechanical force through enzymatic reactions, achieving autonomous propulsion. They have the characteristics of small size, self-propulsion, strong tissue penetration, good selectivity, and good biocompatibility. From crossing biological barriers to targeted drug delivery, they provide a new tool for cancer treatment and have good application prospects.

Various studies focus on the specific catalytic effects of natural enzymes (such as urease, glucose oxidase (GOx), plasma amine oxidase (PAO), etc.) in the tumor microenvironment. In 2020, Choi et al. developed a urease driven polydopamine nanomotor (Fig. 3a) that utilizes high concentrations of urea (100 mM) in the bladder as a natural fuel. Urease catalyzes the decomposition of urea into ammonia and carbon dioxide, driving the nanomotor to penetrate the bladder mucosal layer and achieve long-term retention.⁵⁸ Baptista and others further modified the bowl shaped nano motor driven by urease through antibodies, targeting the 3D bladder cancer sphere, significantly enhancing the drug penetration efficiency in tumor tissue, proving the synergistic advantage of enzyme driven and targeted modification.²⁰ In 2021, the HFLA-Dox core–shell nanomotor designed by Wan innovatively utilized nitric oxide synthase (NOS) to catalyze the production of NO from L-arginine, constructing an enzymatic chemical gradient. The nanomotor actively migrates by sensing the concentration gradient of NO, and at the same time, NO reacts with superoxide anions to generate peroxynitrite (ONOO⁻), which degrades the ECM collagen of tumor cells, achieving the triple function of “enzymatic drive-matrix degradation-drug release”. For the first time, enzymatic reaction is combined with microenvironment responsive therapy.⁴⁵ In 2024, Choi and others developed a chitosan/heparin based urease nanomotor (Fig. 3b), which used urease catalyzed urea to drive the nano motor to enrich bladder tumors. Its porous hydrogel structure will release STING agonists under the trigger of reactive oxygen species (ROS), activate dendritic cells and recruit CD 8⁺ T cells. The therapeutic effect will increase by 94.2% compared with traditional therapy, creating a combined treatment mode of enzyme driven immune activation.⁵⁹ At the same time, Li et al. designed GOx/L-arginine dendritic nanomotors for glioblastoma (Fig. 3c), using GOx to catalyze glucose to generate H₂O₂ and iNOS to catalyze L-arginine to generate NO, constructing a dual enzymatic gradient to drive the nanomotor to penetrate the blood–brain barrier, synchronously release cisplatin, and activate photothermal therapy.⁶⁰ Zhao et al. modified nanoparticles with plasma amine oxidase (PAO) to break down highly expressed polyamines (PAs) in tumors, producing acrolein and H₂O₂, forming a concentration gradient to drive nanomotors to enrich towards the tumor center, induce cell apoptosis and inhibit migration (Fig. 3d),⁶¹ demonstrating the unique advantages of enzymatic response in overcoming tumor drug resistance. Designed by Mei et al. in 2025, MSLA@GOx–PDA nanomotor combines the high glucose metabolism characteristics of tumors and utilizes GOx specific catalysis to generate H₂O₂ from glucose, triggering the release of NO from L-arginine to form a secondary enzymatic gradient. At the same time, it inhibits heat shock proteins through NIR photothermal effect, achieving a synergistic effect of “enzyme driven-photothermal chemotherapy” and converting tumor metabolic signals into enzyme driven forces, providing a new strategy for deep tumor treatment.⁶²

Fig. 3 Applications of enzyme-driven micro/nanomotors in cancer therapy. (A) Urease-driven polydopamine nanomotors. Reproduced with permission from the ref. 58. Copyright 2024, Springer Nature. (B) Enzyme-driven nanomotors activate the immune response. Reproduced with permission from ref. 59. Copyright 2024, Springer Nature. (C) GOx/L-arginine nanomotors utilize GOx and inducible nitric oxide synthase (iNOS) to establish a dual enzymatic gradient. Reproduced with permission from the ref. 60. Copyright 2024, Springer Nature. (D) Plasma amine oxidase (PAO)-modified nanomotors overcome tumor resistance. Reproduced with permission from ref. 61. Copyright 2025, Elsevier.

These studies have constructed a driving system with enzymatic reaction as the core: from the application of early enzyme like catalysis (platinum nanoparticles)⁶³ to natural enzymes (urease, GOx), from single enzyme driven to “enzyme gradient immune/photothermal/chemotherapy” multi-mode synergy, realizing the precise treatment of specific tumors such as bladder cancer and glioblastoma. However, enzymatic reactions are easily affected by fluctuations in tumor microenvironment pH, enzyme activity, and substrate concentration, resulting in insufficient driving force stability. The driving of micro/nanomotors requires stronger mechanism universality. Therefore, future research needs to focus on enzyme engineering modification (such as high-temperature resistant and anti-degradation enzyme design), development of intelligent material carriers, and the development of completely autonomous driving strategies that do not rely on external environmental signals.

3. Physical driven micro/nanomotors

Compared to the substrate reaction driven propulsion mechanism of chemical driven micro/nanomotors, physically stimulated micro/nanomotors (such as light, magnetic, ultrasound and other external control systems) have unique potential in cancer diagnosis and treatment in complex physiological environments due to their non-contact control and adjustable spatiotemporal accuracy. This section will focus on the design principles of physical driving modes such as light/magnetic guidance/acoustic dynamics, and summarize their latest progress and key challenges in tumor targeted delivery, in situ intervention, and integrated diagnosis and treatment.

3.1. Magnetic driven micro/nanomotors

Magnetic particles are one of the most widely used types of physically driven nanomotors. Their movement is guided by an external magnetic field that provides controlled guidance. For example, a rotating magnetic field can be applied to drive these motors, where magnetic vectors rotate at a fixed frequency in space, thereby inducing torque in the magnetic structure. Based on this effect, Fischer et al. developed spiral shaped nanomaterials based on silica heads with magnetic tails that can be guided by external magnets.⁶⁴ These nanothrusters exhibit mobility in various viscous environments, including Newtonian fluids (such as glycerol) and non-Newtonian fluids (such as hyaluronic acid, which have complex rheological properties), promoting research on magnetic driven nanomotors.⁶⁵ The exploration of the application of magnetic driven nanomotors in cancer treatment has always focused on the core requirements of precise targeting and efficient intervention. Through material morphology design, innovative driving mechanisms, and functional modular integration, a multi-level treatment system from macroscopic tissue targeting to microscopic cell regulation has been gradually constructed. As these micro/nanomotors shrink to the size of individual cells, or even smaller, they can enter areas of the body that were previously inaccessible, enabling high-resolution, in situ, and in vivo manipulation. In the field of biological guidance and immune regulation, the soft material motor with both biocompatibility and magnetic control mobility shows unique advantages: the spiral polyethylene glycol (PVA) hydrogel motor developed by Tu et al. constructs a porous structure through rotating needle extrusion, loads superparamagnetic Fe₃O₄ nanoparticles and chemotactic factor CXCL12, and achieves 2.5–3.7 mm s⁻¹ controllable propulsion in 3D space under low intensity magnetic field (Fig. 4a).⁶⁶ This design breaks through the biocompatibility limitations of traditional rigid micro/nanomotors and utilizes the motion advantages of spiral propulsion in highly viscous biological fluids to deliver CXCL12 to the target area, guiding Jurkat T cells to migrate in a targeted manner and providing a flexible carrier paradigm to solve the problem of low migration efficiency of immune cells in vivo. In addition, magnetic driven micro/nanomotors can also accurately deliver therapeutic biomolecules for cancer treatment and other minimally invasive surgeries that require precise manipulation (Fig. 4b).⁶⁷ In the in-depth analysis of the specific recognition mechanism of tumor microenvironment, the study of magnetic driven mechanical responsive nanomotors revealed the adhesion heterogeneity of ECM (Fig. 4c). Ghosh et al. found that the adhesive force (10–40 nN) of the silica based spiral nano motor (50 nm in diameter) near the breast cancer cell MDA-MB-231 was significantly higher than that of the normal cell HMLE.⁶⁸ Its adhesive mechanism was derived from the sialic acid sugar molecules secreted by the cancer cells modified the ECM, making the ECM surface rich in negative charge groups, while the surface of the unmodified silica based nanomotor had a weak positive charge due to the dissociation of the silicon hydroxyl group, and the two produced specific adhesion through the electrostatic attraction of positive and negative charges. This is also the first time that the influence of the physicochemical heterogeneity of the tumor microenvironment on the localization of nanomotors has been verified from a mechanical perspective, laying a theoretical foundation for the development of targeted strategies coupled with environmental response magnetic navigation. In addition, magnetic nanomotors with sensing capabilities can achieve responsive drug release, providing patients with more personalized and optimized treatment plans.^69,70 At the level of energy conversion and synergistic therapy, the morphology engineering of nanoparticles has become a key breakthrough in improving the effectiveness of magnetic hyperthermia. The systematic study by Liang et al. showed that Mg doped γ–Fe₂O₃ nanoparticles (7 nm core) optimized the magnetic crystal anisotropy through cation doping, resulting in an intrinsic loss power (ILP) of 14 nH m² kg⁻¹.⁷¹ Under a 400 kHz magnetic field, it induced a local temperature rise of over 43 °C in the tumor and triggered cancer cell apoptosis. But due to the ordering of surface spin structures, the cubic Zn_0.4Fe_2.6O₄ nanoparticles (18 nm edge length) exhibit a saturated magnetization increased to 165 emu g⁻¹. The specific surface area effect enhances their specific absorption rate (SAR) by 30% compared to spherical particles. After loading Dox, these nanoparticles achieve synchronous thermal damage and drug release under an alternating magnetic field, verifying the synergistic optimization strategy among nanomorphology, magnetothermal efficiency, and drug delivery. Going deeper, the challenge of precise manipulation within cells has opened up new directions for mechanical disruption mechanisms based on cluster adaptive motion. The cubic Zn doped Fe₃O₄ nanomotor (60 nm diameter) designed by Cheng et al.⁷² targets cancer cells with high expression of integrins on its surface with RGD peptides (Fig. 4d). It assembles into rod-shaped aggregates under a magnetic field of 5–15 Hz, and its rotation induced lysosome vortex speed reaches 7.59 μm s⁻¹, leading to increased membrane permeability and caspase-3 activation. This study found that at the critical frequency (20 Hz), aggregates undergo a transition from synchronous rotation to dynamic reconstruction. This frequency adaptive behavior increases energy conversion efficiency by 40%. The apoptosis rate of cancer cells is significantly enhanced compared to the single hyperthermia or mechanical stimulation group, revealing the precise regulatory potential of the coupling law between magnetic field parameters and micro/nanomotor cluster behavior for intracellular mechanical intervention.

Fig. 4 Applications of magnetically-driven micro/nanomotors in cancer therapy. (A) Helical poly(vinyl alcohol) (PVA) hydrogel motors use helical propulsion to deliver CXCL12. Reproduced with permission from the ref. 66. Copyright 2021, Wiley. (B) Magnetically guided carboxyl-functionalized paramagnetic beads for targeted drug delivery and anticancer therapy. Reproduced with permission from ref. 67. Copyright 2023, Wiley. (C) Adhesion force of silica-based helical nanomotors near cancer cells is significantly higher than that near normal cells. Reproduced with permission from the ref. 68. Copyright 2020, Wiley. (D) Zn-doped Fe₃O₄ nanomotors disrupt cancer cells via mechanical stimulation under a magnetic field. Reproduced with permission from ref. 72. Copyright 2021, American Chemical Society.

From material design to mechanism innovation, these studies collectively outline the evolutionary logic of magnetic driven micro/nanomotors in cancer treatment: early macroscopic magnetic navigation provides a carrier for immune regulation, then tumor specific enrichment is achieved through microenvironmental adhesion mechanisms, and energy conversion efficiency is improved through morphology optimization, ultimately developing precise intracellular manipulation based on cluster behavior. Each strategy is not isolated, but presents a trend of technological intersection – such as the combination of chemokine loading and magnetic hyperthermia, the synergy of ECM adhesion and mechanical disruption, which is driving the evolution of this field from a single function to a multimodal treatment system. Future research can further focus on the quantitative relationship between magnetic field parameters and biological response, the long-term biological safety of micro/nanomotors, and in vivo dynamic monitoring technology, accelerating the key leap from laboratory to clinical translation.

3.2. Ultrasonic driven micro/nanomotors

Ultrasound, as an energy with good directionality, strong penetration ability, and minimal harm to the human body, has been widely used in improving cancer treatment.⁷³ Ultrasonic driven micro/nanomotors have also attracted great attention from scientists.⁷⁴ The innovative design and functional integration of ultrasound driven nanomotors provide a cross scale intervention strategy for cancer treatment. Relevant research presents multidimensional applications in cancer treatment, from molecular delivery, tissue penetration to microenvironment regulation, by regulating material morphology, driving mechanism, and loading function. In the field of drug delivery and release, Duan et al. constructed a H₂O₂/ultrasound dual driven nanomotor (CS-ID@NMs) (Fig. 5a).⁷⁵ Using mesoporous manganese dioxide (MnO_x) as the core, silk fibroin and chitosan sulfate (CS) were surface modified. MnO_x was used to catalyze the generation of oxygen bubbles from excess H₂O₂ in the tumor microenvironment. Combined with the acoustic flow effect generated by 1.5 W cm⁻² ultrasound, mucus penetration and deep tumor penetration were achieved. Ultrasound triggered release of indocyanine green derivatives (ID), combined with sonodynamic therapy (SDT), demonstrates the advantages of ultrasound-driven micro/nanomotors in the controlled release and synergistic therapy of targeted drugs. Lu et al. developed a high intensity focused ultrasound (HIFU) driven nanomotor (NP-G/P) aimed at the treatment challenge of triple negative breast cancer (TNBC) (Fig. 5b).⁷⁶ With PLGA nanospheres as the core, they loaded perfluorooctyl bromide (PFOB) and gambogic acid (GA) and modified PEG. HIFU upregulates the expression of iron death related genes (such as SLC7A11 and FTH1) in tumor cells through mechanical stress and thermal effects, enhancing cell sensitivity to GA. High frequency sound waves, especially in the MHz range, are a powerful particle manipulation tool that solves the problem of siRNA delivery. The Janus structured gold nanowire (AuNW) motor designed by Zhang et al. utilizes surface modified polylysine (PLL) loaded perfluorocarbon nanoemulsion (RBC–PFC) wrapped around red blood cell membrane to form a Motor PFC system (Fig. 5c),⁷⁷ which combines high oxygen carrying capacity and ultrasound responsive motion characteristics of the nanomotor. In a 1.0 MHz, 2.5 W cm⁻² ultrasound field, the motor moves directionally at a speed of 4.5 μm s⁻¹, and its mechanism lies in the inertial cavitation effect driven by ultrasound to improve siRNA transfection efficiency. The use of acoustic flow effect to penetrate the ECM of tumor cells, combined with the sustained oxygen release ability of PFC, effectively alleviates the cellular hypoxic microenvironment and provides a dynamic delivery platform for gene therapy of hypoxia dependent tumors.

Fig. 5 Applications of ultrasound-driven micro/nanomotors in cancer therapy. (A) Mesoporous manganese dioxide (MnO_x) nanomotors (CS-ID@NMs) utilize O₂ bubbles and ultrasonic acoustic streaming effects to achieve mucus penetration and deep tumor infiltration. Reproduced with permission from the ref. 75. Copyright 2022, Wiley. (B) High-intensity focused ultrasound (HIFU)-driven nanomotors (NP-G/P) promote cellular ferroptosis. Reproduced with permission from ref. 76. Copyright 2024, Wiley. (C) Janus gold nanowire (AuNW) motors utilize ultrasound to achieve hypoxia-dependent tumor gene delivery. Reproduced with permission from the ref. 77. Copyright 2019, American Chemical Society. (D) Janus Au NR-mSiO₂/AIPH nanomotors utilize acoustic streaming effects and bubble recoil forces to enable the nanomotors to overcome the tumor interstitial barrier. Reproduced with permission from ref. 78. Copyright 2021, Springer Nature.

Ultrasound drive plays a crucial role in breaking through the interstitial fibrosis barrier of tumors, while enhancing the integration of diagnosis and treatment. The Janus Au NR mSiO₂/AIPH nanomotor developed by Su et al.⁷⁸ was partially coated with mesoporous silica (mSiO₂) on the surface of gold nanorods by wet chemical method, and loaded with AIPH to form a dumbbell shaped structure (Fig. 5d). The motor utilizes AIPH decomposition to generate nitrogen microbubbles under 1.0 MHz ultrasound, and its driving mechanism combines acoustic flow effect and bubble recoil force, promoting the nanomotor to break through the tumor interstitial barrier while inducing mechanical damage to the cell membrane. The NIR-II photoacoustic imaging characteristics of alloy nanorods were studied, and the system achieved PA/US dual-mode imaging of deep tissues in the MCF-7 tumor model, verifying the feasibility of ultrasound driven nanomotors in precision treatment of large tumors.

Ultrasonic driven micro/nanomotors have broken through the penetration limitations of traditional passive delivery by optimizing morphology (such as Janus structure, mesoporous loading) and innovating energy conversion mechanisms (acoustic energy to mechanical energy, ultrasound induced gas drive), demonstrating two core advantages. Firstly, by utilizing the deep penetration characteristics of ultrasound, the nanomotor is driven to actively migrate in the highly viscous tumor microenvironment, achieving directional delivery of drug and gas; secondly, it can integrate imaging and treatment functions using NIR-II photoacoustic imaging to locate deep tumors, combined with ultrasound triggered SDT and gas therapy, to form a collaborative system of precise positioning and efficient intervention. From basic intracellular O₂ transport to complex multimodal treatment of large tumors, these studies not only reveal the universality of ultrasound driven micro/nanomotors in structural design and functional integration, but also highlight their clinical translational potential in overcoming tumor heterogeneity and improving treatment depth and accuracy.

3.3. Light driven micro/nanomotors

Light driven micro/nanomotors achieve autonomous motion by converting light energy into mechanical driving force, and their operation depends on the asymmetric field effects of the surrounding environment, such as light intensity gradients and differences in photothermal response.⁷⁹ This type of motor has the characteristics of wireless control, precise and adjustable energy input, and reversible light response switch, which can achieve high-precision spatiotemporal motion control and non-invasive operation, demonstrating unique advantages in the field of cancer treatment.⁸⁰ The design based on photocatalytic active materials is an important pathway for constructing such motors. Typical materials include TiO₂,⁸¹ Ag₂S,⁹ single atom copper,²¹etc. Their light absorption properties can effectively mediate the conversion of light energy to mechanical energy.

The evolution of driving light sources is a key breakthrough in this field - from early penetration of shallow and biologically damaging ultraviolet light, gradually expanding to long wavelength visible light (400–760 nm) and NIR light (760–1700 nm), significantly improving tissue penetration depth and application safety.⁸² The visible light driven system (such as 400–760 nm) has unique advantages in precision treatment of superficial tumors due to its low tissue scattering and good biocompatibility. For example, Cai et al. developed the Cu₂O@N-CNTs micromotor (Fig. 6a),⁸³ which uses 510–560 nm green light to excite the Cu₂O photocatalytic decomposition of glucose to produce a concentration gradient that drives the motor to swim at a speed of 18.71 μm s⁻¹. This mechanism does not rely on enzyme fuels and can continue to operate in a glucose rich tumor microenvironment, avoiding the damage of traditional ultraviolet light to normal tissues. The Janus microcar constructed by Pacheco et al. uses CdTe quantum dots as the photoactive material,⁸⁴ which excite electron transfer to the Fe₃O₄ catalytic patch under visible light at 470–490 nm (Fig. 6b). It actively searches and removes bacterial endotoxins in complex media such as serum through diffusion electrophoresis. The biocompatibility of its polycaprolactone film layer and the low-energy input driven by visible light provide a safe and efficient platform for targeted detoxification in superficial areas.

Fig. 6 Applications of light-driven micro/nanomotors in cancer therapy. (A) Cu₂O@N-CNT micromotors utilize 510–560 nm green light to excite photocatalytic decomposition of glucose. Reproduced with permission from the ref. 83. Copyright 2019, American Chemical Society. (B) Janus microcars employ CdTe quantum dots for electron transfer to Fe₃O₄ catalytic patches upon visible light excitation. Reproduced with permission from ref. 84. Copyright 2019, Wiley. (C) Se&PMO Janus nanomotors generate Au-induced thermophoretic force under 808 nm light to penetrate dense tumor stroma. Reproduced with permission from the ref. 85. Copyright 2025, American Chemical Society. (D) Macrophage membrane-camouflaged Janus nanomotors utilize the photothermal effect of Au hemishell under 808 nm light to induce transient cell membrane perforation. Reproduced with permission from ref. 87. Copyright 2018, Wiley.

The NIR light driven system (such as 800–1000 nm) has become the core direction of deep tumor treatment due to its deeper tissue penetration ability (up to centimeter level). The Se&PMO Janus nanomotor (Fig. 6c) designed by Li et al. regulates the exposure rate of selenium subunits (0–75%) through dual ligands.⁸⁵ Under 808 nm light, a thermal gradient is generated by the Au half shell, which induces thermophoretic forces to penetrate the dense tumor stroma. Combined with the high drug loading pores of mesoporous organosilicon (pore size ∼2 nm), it achieves targeted delivery of hydrophobic drugs (such as disulfiram) and photothermal synergistic therapy. Macrophage membrane camouflage Janus nanomotor developed by Xuan et al.¹⁹ utilizes the surface plasmon resonance effect of Au half shell under 808 nm light to actively approach cancer cells at a speed of 1.46 μm s⁻¹ in fetal bovine serum. The cell membrane camouflage technique reduces non-specific protein adhesion by 60%, and its photothermal effect (heated to 57 °C) can induce transient cell membrane perforation, promote the infiltration of macromolecular dyes such as propidium iodide, and provide a new mechanical thermal synergistic strategy for membrane permeation therapy of deep tumors. Van Hest and his colleagues reported a nanomotor system where gold nanoparticles are loaded into “bowl-shaped” polymeric vesicles. Driven by NIR photothermal conversion, this nanomotor achieves a maximum speed of 125 μm s⁻¹, representing a new breakthrough in nanomotor motility.⁸⁶

This expansion of light sources from ultraviolet to visible/NIR light not only solves the tissue penetration limitations of traditional short wavelength light, but also achieves functional upgrades through material design. The visible light driving system focuses on shallow precision operation and biocompatibility, such as using natural glucose within the tumor microenvironment as an energy source to continuously generate product gradients under visible light, achieving targeted adhesion and drug release to tumor cells. The NIR drive system focuses on deep intervention, such as Zhou et al.'s IBR loaded nanomotor (Fig. 6d),7 which breaks through the vascular barrier through 808 nm light drive and delivers drugs to M2 macrophages, inhibiting the BTK signaling pathway and inducing polarization towards M1, increasing the secretion of pro-inflammatory factors such as IL-12 by 2.5 times, and achieving a tumor inhibition rate of 97.9% in vivo. The mPPy@COF-Por nanomotor developed by Feng et al. integrates a 660 nm visible light-induced photodynamic effect (generating reactive oxygen species) and an 808 nm NIR-driven photothermal effect (temperature rising to 51.3 °C).⁸⁸ Through cancer cell membrane camouflage for homologous recognition, it penetrates 70 μm-deep tumor tissue under the guidance of three-modal imaging and synchronously completes combined therapy of “diagnosis-thermal ablation-oxidative damage”, demonstrating the multidimensional intervention capability of light-controlled driving in complex tumor microenvironments.

In summary, the evolution of light sources and material innovation in light driven micro/nanomotors complement each other. Visible light systems rely on biocompatibility and surface precision to explore new scenarios for shallow targeting and cell manipulation. The NIR system overcomes the challenges of deep tumor penetration and efficient treatment through deep penetration and thermal effects. The two have jointly constructed a technology matrix from the surface to the deep layer, from a single delivery carrier to an intelligent diagnosis and treatment platform, providing a systematic solution to break through the accuracy and safety bottlenecks of traditional cancer treatment.

4. Multifield coupling driven micro/nanomotors

In the exploration of using micro/nanomotors for cancer treatment, a single chemical drive relies on the stability of the tumor microenvironment material gradient, while physical drive is limited by the depth of external field penetration or tissue compatibility. The sustained movement and targeted accuracy of both in complex physiological environments face bottlenecks. In this context, multi field coupling driven micro/nanomotors have become a key direction for breaking through the barriers of deep tumor therapy by integrating multiple energy conversion mechanisms.

As the most important multifield driving method, the cooperative driving of chemical energy and light energy integrates two forms of energy to achieve efficient movement and treatment functions, showing unique advantages. Chen et al. built a dual source driven Janus nanomotor with mesoporous silica as the core,⁸⁹ with single-sided sputtering gold layer to form an asymmetric structure, loaded with catalase and photosensitizer TAPP (Fig. 7a) to achieve the cooperative driving of chemical energy and light energy, and achieve photothermal/photodynamic collaborative treatment in the 4T1 breast cancer model, with a tumor inhibition rate of 90.3%, laying an important foundation for the construction of a dual energy driving system. Following this research approach, the CuS/Pt Janus nanomotor designed by Wang et al.⁹⁰ further optimized the synergistic mechanism, utilizing the chemical driving force of Pt catalyzed H₂O₂ to generate O₂ and the photothermal driving force of CuS to form a synergistic effect of O₂ bubble propulsion-thermophoretic enhancement under 808 nm light, deeply penetrating tumors. These cases demonstrate that the deep coupling of chemical and photothermal driving can significantly enhance the tumor penetration ability and therapeutic efficacy of micro/nanomotors. On the basis of chemical photothermal synergistic driving, researchers further explored composite driving strategies that combine tumor microenvironment response, such as the parachute shaped Au₂Pt@PMO@ICG nanomotor designed by Zhang et al. adopts a chemical-thermophoretic dual driving force and also constructs an environment responsive functional network (Fig. 7b).⁸² In the acidic tumor microenvironment, the Au₂Pt bimetallic nanozyme not only catalyzes the decomposition of H₂O₂ to generate O₂ (chemical driving force) and ˙OH (initiating chemodynamic therapy, CDT), but also utilizes O₂ to relieve tumor hypoxia and activate indocyanine green (ICG)-mediated photodynamic therapy (PDT). Meanwhile, the thermophoretic force induced by NIR light (physical driving force) forms a synergistic loop of microenvironment triggering -multimodal therapy-directional movement with the above-mentioned chemical response processes. On this basis, Zhang et al. further integrated multiple driving mechanisms and constructed a “core–shell satellite” asymmetric structure (Fig. 7c).⁹¹ Platinum nanoparticles and polyacrylic acid grafted gold nanoparticles were loaded on one side of a mesoporous silica core, forming a pH responsive Janus nanomotor. JMSNs@Pt@P–Au achieves consistent movement direction and deep-tumor penetration through triple-dynamic synergy, including the self-diffusiophoresis of Pt-catalyzed H₂O₂ in a neutral environment, self-electrophoresis triggered by an acidic environment, and the NIR photothermal phoresis effect. This breakthrough goes beyond the binary framework of simple energy synergy and provides new ideas for the precise intervention of complex tumor microenvironments. In the field of targeted delivery and microenvironment regulation, the introduction of bioactive ingredients has opened up new directions. The bioactive nanomotor developed by Wang et al.⁹² camouflages the mesoporous silica/polydopamine (MSN/PDA) Janus structure with the cell wall of Lactobacillus rhamnosus (CWL) (Fig. 7d), and combines NO gas driving with NIR thermophoresis. The CWL targets IgA at the colorectal tumor site. Under NIR irradiation, PDA–BNN6 releases NO to activate the cGMP/PKG signaling pathway. NIR light (808 nm) triggers NO release from nanomotors, which inhibits RhoA/ROCK by activating the cGMP/PKG pathway, downregulates tight junction proteins (e.g., claudin-1 and occludin), widens epithelial cell gaps, and reversibly opens the paracellular pathway. Meanwhile, the photothermal effect of NIR light and recoil force of NO gas synergistically drive nanomotors to penetrate the mucus barrier, enhancing cisplatin delivery efficiency. In vivo experiments show that this combination therapy improves the tumor microenvironment by inhibiting the HIF-1α/VEGF pathway, activates c-caspase-3 to induce tumor cell apoptosis. Meanwhile, the thermophoretic effect promotes the movement of the nanomotor in the mucus layer, achieving a deep integration of biological targeting and functional driving. This provides a breakthrough solution for the treatment of tumors with abundant mucus barriers and demonstrates the unique advantages of bioactive driving in complex physiological environments. These cases demonstrate the design innovation of Janus micro/nanomotors from different dimensions, jointly revealing the importance of multimodal driving mechanisms and collaborative treatment strategies. In the future, modular design of driving mechanisms, optimization of biocompatibility, and clinical translation pathways can be further explored to accelerate the development of micro/nanomotor technology from basic research to practical applications in precision medicine.

Fig. 7 Applications of multifield-coupled driven micro/nanomotors in cancer therapy. (A) Janus mesoporous silica nanomotors loaded with catalase and photosensitizer TAPP achieve synergistic driving of chemical energy and light energy. Reproduced with permission from the ref. 89. Copyright 2022, Elsevier. (B) Parachute-shaped Au₂Pt@PMO@ICG nanomotors utilize microenvironment-triggered O₂ (chemical driving force) and NIR light-induced thermophoretic force (physical driving). Reproduced with permission from ref. 82. Copyright 2024, Wiley. (C) pH-responsive Janus nanomotors JMSNs@Pt@P–Au achieve deep tumor penetration through triple-driven synergy—self-diffusiophoresis, self-electrophoresis, and NIR photothermophoresis. Reproduced with permission from the ref. 91. Copyright 2025, Elsevier. (D) Lactobacillus rhamnosus cell wall (CWL)-camouflaged mesoporous silica/polydopamine (MSN/PDA) Janus nanomotors integrate NO gas propulsion and NIR thermophoresis. Reproduced with permission from ref. 92. Copyright 2025, Springer Nature.

These studies collectively indicate that multifield coupling driving not only solves the problems of inconsistent motion direction and insufficient penetration ability of traditional micro/nanomotors, but also achieves dynamic response to the tumor microenvironment (pH, H₂O₂ concentration, temperature) through material surface functionalization and integration of therapeutic modules. From dual source collaboration to triple composite drive, innovative practices in this field continue to drive the evolution of nanomotors from a single functional carrier to an integrated platform of environmental response-intelligent navigation-multimodal therapy, which is expected to accelerate the paradigm shift of cancer treatment from extensive killing to precise and intelligent intervention.

5. Biological hybrid micro/nanomotors

Nature has always provided innovative inspiration for humanity. In addition to the two types of artificial micro/nanomotors mentioned above, the chemotaxis or affinity of biological systems, such as whole cells or natural living microorganisms, can also be utilized to prepare self-propelled micro/nanomotors. Biological hybrid micro/nanomotors refer to motors that contain biological components (such as DNA, enzymes, cell membranes, and cells) and artificial components (such as inorganic or polymer particles). They can inherit the biological characteristics, onboard driving and sensing abilities of their parents.⁹³ These living systems can act as engines that generate propulsion, perceive stimuli in the surrounding environment, and move towards attractants.⁹⁴ Early research has established a diverse structural paradigm for bio-hybrid micro/nanomotors, such as DNA nanorobots, enzyme based motors, and cell-derived carriers.⁹⁵ Among them, DNA nanorobots self-assemble into whip bundles through complementary oligonucleotides and combine with magnetic particles to achieve external magnetic field driving; enzyme based motors generate directional driving force by utilizing the energy released from enzyme catalyzed reactions; Cell derived carriers such as ultrasound nanomotors wrapped in red blood cell membranes integrate the controllable properties of artificial materials through the natural targeted recognition ability of cell membrane surface antigens. These systems lay the foundation for the bio-artificial hybrid system by synergistically combining the biological functions of biological components (such as targeting and mobility) with the physical and chemical properties of artificial materials (such as magnetic field response and carrier stability), providing key design ideas and technical support for subsequent targeted drug delivery and cancer treatment research. Magnetic orientation and chemotaxis have become the two core strategies driving mechanism innovation. Among them, sports bacteria are an ideal engine for driving micro/nanomotors, and there are also many related studies.^96,97 The magnetic directional bacterial micromotor developed by Felfoul et al.⁹⁶ utilizes the magnetic and oxygen chemotaxis characteristics of Magnetococcus marinus MC-1 bacteria to target drug loaded nanoliposomes to hypoxic areas of tumors through magnetic navigation (Fig. 8a). The magnetic body chains on the bacterial membrane surface are guided to move under an external magnetic field, while the natural chemotaxis of bacteria enhances their ability to locate the hypoxic microenvironment, achieving 55% cell aggregation in hypoxic areas of tumors and providing a new pathway for targeted therapy for hypoxia. To complement it, Shao et al. constructed a chemotactic neutrophil micromotor8 that wraps mesoporous silica nanoparticles (MSNs) in Escherichia coli (E. coli) membranes (Fig. 8b). By utilizing the natural chemotactic ability of neutrophils to respond to the chemical gradient secreted by bacteria, the membrane camouflage strategy increased the intracellular uptake rate of nanoparticles to 97.36% and maintained cell activity of over 80%. This proves that the chemotactic movement of biological cells can be directly converted into directional driving force, providing biogenic power for dynamic targeting of inflammation or tumor sites.

Fig. 8 Applications of bio-hybrid-driven micro/nanomotors in cancer therapy. (A) Chemotactic neutrophil micromotors constructed by coating mesoporous silica nanoparticles (MSNs) with E. coli membranes. Reproduced with permission from the ref. 96. Copyright 2016, Springer Nature. (B) Biomimetic hybrid membrane nanocarriers (CCMpHD) utilize membrane protein homologous targeting to recognize tumor cells. Reproduced with permission from ref. 98. Copyright 2017, Wiley. (C) Biomimetic hybrid membrane nanocarriers (CCMpHD) utilize membrane protein homologous targeting to recognize tumor cells. Reproduced with permission from the ref. 99. Copyright 2024, Wiley. (D) Bio-adhesive bacterial microswimmers utilize the lectin-mannose interactions of E. coli type I pili to provide bio-adhesive strategies for gastrointestinal and urinary tract targeting. Reproduced with permission from ref. 97. Copyright 2017, Wiley.

The combination of biomimetic membrane camouflage and intelligent responsive materials significantly improves delivery efficiency in cancer treatment applications. The biomimetic hybrid membrane nanocarrier (CCMPHD) designed by Chen et al.⁹⁹ combines tumor cell membranes with pH sensitive liposomes, utilizing homologous targeting of membrane proteins to recognize tumor cells (Fig. 8c). At the same time, liposomes trigger membrane fusion and release drugs in acidic tumor microenvironments, demonstrating the synergistic advantages of biofilm functionalization and intelligent responsive materials. Microbial driven nanomotors demonstrate unique advantages in targeted delivery. Mostaghaci et al. constructed a bio-adhesive bacterial microswimmer⁹⁷ that utilizes the lectin mannose interaction of E. coli type I pili to specifically attach fluorescent dye loaded polymethyl methacrylate particles to the surface of mannose expressing cells (Fig. 8d). In vitro experiments have shown that its adhesion density is more than 10 times higher than that of unmodified particles, providing a bio-adhesion strategy for gastrointestinal and urinary tract targeting. Combined with the natural motility of bacteria, it achieves local drug enrichment. Huang et al. revealed the chemotaxis driven Janus particle movement mechanism through molecular dynamics simulations,4 and found that changes in stimulus intensity caused particles to transition from compound random walk to directional movement, providing theoretical support for the rational design of controllable nanomotors driven by bacteria.

These studies collectively indicate that the development of bio-hybrid driven micro/nanomotors is moving from single component integration to multimodal collaboration: cell membrane camouflage solves targeting and immune escape, biological mobility provides power, external field control or microenvironment response enhances precision, while advances in materials science (such as degradable carriers and intelligent release mechanisms) continue to optimize treatment safety. With the deep integration of gene editing technology (such as CRISPR modified bacteria) and nanomanufacturing, such systems are expected to make breakthroughs in precision targeting, in situ drug generation, and real-time integrated diagnosis and treatment, bringing revolutionary strategies to cancer treatment.

6. Conclusions and prospects

This review focuses on the application of micro/nanomotors in cancer treatment and explores their various driving methods and development processes. From chemical driven, physical driven, multi field coupling driven to bio-hybrid driven, various micro/nanomotors have shown great potential in tumor targeted delivery, drug release regulation, immune activation, and integrated diagnosis and treatment due to their unique motion mechanisms and functional characteristics. Chemical driven micro/nanomotors utilize endogenous or exogenous substances in the tumor microenvironment to achieve active chemotaxis. Physical driving technology utilizes precise control of external fields such as magnetism, ultrasound, and light. Multi field coupling driven integration of multiple energy sources enhances therapeutic efficacy. Biological hybridization drives the fusion of biological functions and the advantages of artificial materials. Each has its own unique pros and cons. These characteristics are summarized in Table 1. It is worth noting that this table is only an empirical summary and represents most of the cases. These advances provide new ways to overcome the challenges of cancer treatment and promote the development of cancer treatment towards precision and efficiency.

Table 1 Summary of the propulsion strategies for micro/nanomotors with the corresponding characteristics

Driving type		Energy/substrate	Advantages	Disadvantages	Application scenarios	Ref.
Chemical driving	Bubble	Propulsion Gases such as H2O2, NO, and SO2	1. High speed (e.g., 34.3 μm s^−1), no external energy required	1. Adsorption of blood components reduces speed	Colorectal cancer treatment, tumor microenvironment regulation, and enhanced deep chemotherapy delivery	23–26 and 42–47
			2. Enables multimodal photothermal/chemotherapy integration	2. Fluctuating fuel concentration in the tumor microenvironment affects driving force
	Self-electrophoretic driving	Ion concentration gradient	1. Autonomous movement, adapts to complex physiological environments	1. Catalytic surface stability needs optimization	Immune activation, intracellular mechanical intervention in tumor cells	30–32 and 48–54
			2. Activates immune responses (e.g., piezo1 channels)	2. Blood protein corona interferes with electrochemical reactions
	Enzyme Driving	Urea, glucose, L-arginine	1. Good biocompatibility, uses endogenous fuel	1. Enzyme activity affected by pH/substrate concentration	Bladder cancer, glioblastoma treatment, gene therapy delivery	38–42 and 55–62
			2. Integrates immune activation (e.g., STING agonists)	2. Insufficient driving force stability limited by substrates
Physical driving	Magnetic driving	External magnetic field	1. Remote precise navigation, multi-degree-of-freedom control	1. Difficult to drive micrometer-scale motors	Tumor-targeted delivery, immune cell guidance, mechanical intervention of the tumor microenvironment, specific adhesion and enrichment of tumor tissues	44–48, 52 and 64–72
			2. Recyclable, avoids in vivo accumulation.	2. Interferes with clinical examinations like MRI
				3. Limited by the penetration depth (1–3 cm), restricted application in deep tumors
	Ultrasound Driving	Ultrasound waves	1. Strong penetration (deep tissues), good biocompatibility	1. Limited types of sound-activated nanomaterials	Triple-negative breast cancer treatment, gene delivery	55–58 and 73–78
			2. Triggers drug release	2. Limited by the penetration depth (<5 cm), restricted application in deep tumors
	Light driving	Near-infrared (NIR) light	1. NIR penetration depth reaches the centimeter level	Limited light penetration depth (<2 cm), restricted application in deep tumors	Superficial tumor treatment, photothermal/photodynamic synergy	64–68, 72 and 79–88
			2. Precisely regulates movement and drug release
Multi-Field Driving	Chemical-Photothermal Coupling	NIR light + H2O2/NO	1. High penetration efficiency	1. Complex preparation process	Colorectal cancer treatment, multimodal tumor ablation	63, 71, 72,82 and 89–92
			2. Responds to tumor microenvironment (pH, hypoxia)	2. Complex mechanism
				3. Biological safety needs optimization
Biohybrid driving	Bacteria/cell membrane camouflage	Biological chemotaxis (e.g., neutrophils, E. coli)	1. Natural targeting (e.g., IgA recognition), low immunogenicity	1. Poor movement controllability	Tumor microenvironment targeting, inflammatory site intervention	76–79 and 93–99
			2. Responds to biological signals (e.g., inflammatory factors)	2. Potential biosafety risks (e.g., bacterial toxicity)
				3. Tumor microenvironment targeting, inflammatory site

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Notably, the active motility of micro/nanomotors not only provides core driving force for breaking through tumor microenvironment barriers but also demonstrates unique value in overcoming multiple biological barriers across interdisciplinary applications. For example, the bionic nanomotor Pt@LF generates self-propulsive force through Pt nanozyme-catalyzed decomposition of H₂O₂ into oxygen bubbles, achieving efficient brain targeting. This alleviates the predicament where neuroprotective drugs struggle to reach deep ischemic and hypoxic brain regions due to the obstruction of the blood–brain barrier and the “no-reflow” phenomenon.¹⁰⁰ In the process of antifungal therapy, the skin stratum corneum and fungal biofilms also form barriers to drug delivery. Lin and his colleagues reported a NIR laser-propelled umbrella-shaped nanomotor (PNM), whose self-thermophoretic propulsion and photothermal effect play a crucial role in breaking through the stratum corneum barrier, promoting fungal uptake, and enhancing biofilm adhesion.¹⁰¹ The active motility of micro/nanomotors not only shows unique advantages in drug delivery through biological barriers but also opens up innovative application scenarios in interdisciplinary fields. Through dynamic microenvironment regulation mechanisms, they exhibit great potential in tissue regeneration, disease diagnosis, and environmental monitoring. Firstly, micro/nanomotors enable tissue regeneration via dynamic microenvironment regulation. For instance, Guan's team developed semi-coated Janus mesoporous silica nanomotors that target the hyperglycemic region of diabetic wounds, remodel microenvironmental pH and oxygen levels, and accelerate wound healing.¹⁰² In the field of cancer diagnosis, enzyme-triggered DNA nanomotors can analyze the activity of extracellular vesicle-associated or free apurinic/apyrimidinic endonuclease 1 in various biological samples, enabling early cancer diagnosis.¹⁰³ In biosensing, responsive self-propelled nanomotors can be used for rapid concentration and detection of ultra-low-concentration emerging pollutants. For example, thermosensitive polymer-coated magnetic ring-shaped iron oxide nanomotors can dynamically capture trace emerging pollutants through multiple adsorption interactions under an external magnetic field.¹⁰⁴ These non-cancer therapeutic applications not only expand the technical boundaries of micro/nanomotors but also highlight their expansion from cancer therapy to broader life science fields.

As the application potential of micro/nanomotors in the biomedical field becomes increasingly prominent, their biocompatibility has attracted widespread attention, prompting extensive research in this area. Recently, preliminary studies have revealed the short-term metabolic pathways and safety profiles of micro/nanomotors in vivo. For example, zinc micromotors developed by Peng's team have demonstrated positive efficacy in hepatic encephalopathy models: they not only effectively reduce blood ammonia levels through metabolic pathways but also showed no obvious liver tissue damage in short-term observations, providing experimental evidence for the safety of their short-term application.¹⁰⁵ Although such short-term studies have laid a foundation for researching the biosafety of micro/nanomotors, overall, exploration into their long-term biocompatibility remains in its initial stages. As a core indicator for evaluating the clinical application value of micro/nanomotors, the long-term risks to biosafety cannot be ignored. At present, there is still a lack of systematic and in-depth scientific understanding regarding the long-term accumulation patterns of micro/nanomotors and their degradation products in metabolic organs such as the liver, as well as their potential impacts on lipid metabolism and drug-metabolizing enzyme systems, necessitating more comprehensive experimental verification and data support. From a methodological perspective, existing research data are mostly derived from short-term animal experiments, while key research components—such as dynamic monitoring of metabolites at different time points and long-term tracking analysis of histopathology and metabolomics—remain limited. Therefore, future studies could focus on establishing a multi-dimensional, long-term in vivo monitoring system to comprehensively evaluate the biotransformation behaviors and potential risks of micro/nanomotors during long-term circulation by continuously tracking their entire process of distribution, metabolism, and degradation in organisms. Furthermore, as an important excretory organ in the human body, the kidneys play a crucial role in maintaining internal environmental homeostasis. Existing studies have observed that nanoparticles of specific sizes can accumulate in the kidneys.¹⁰⁶ However, research on the long-term accumulation kinetics of micro/nanomotors—endowed with active motility—in the kidneys is still in the exploratory stage. Given that the active movement of micro/nanomotors may alter their transport pathways during renal filtration and reabsorption, it is necessary to conduct multi-time-point dynamic monitoring and systematic studies on the impact on the glomerular filtration rate and renal tubular function to fully reveal their long-term effects on renal function.

Based on current literature, although micro/nanomotors have shown advantages in preliminary explorations of disease treatment, multi-dimensional and long-time-scale studies are urgently needed before their clinical translation. On one hand, it is necessary to establish long-term animal experimental models and utilize advanced detection technologies, such as high-resolution mass spectrometry imaging, to continuously monitor the concentration changes of micro/nanomotors and their metabolites in the liver and kidneys, and map long-term accumulation curves. On the other hand, long-term tracking should be conducted from the molecular level (e.g., inflammatory factor profiles), cellular level (immune cell activity) to the organ level (tissue pathological sections) to deeply explore the changes in molecular mechanisms caused by their long-term accumulation in organs, and reduce the risk of residual metal components through the design of degradable materials. Meanwhile, in the practical application of cancer treatment, the clinical translation of micro/nanomotors still faces multiple key limitations, and systematic solutions need to be constructed around the core obstacles exposed in animal model validation. For example, to address the limitation of tissue penetration depth (<2 cm) of near-infrared light-driven systems in tumor models, the application boundary can be expanded through multi-field coupling driving strategies, such as the synergy between magnetic-driven remote control and light-driven penetration. There are an urgent need to break through technical bottlenecks through interdisciplinary research:

(1) Insufficient precision in motion control: although existing nanomotors can regulate their motion direction and speed through external field regulation (e.g., magnetic fields and light fields) and chemical reaction catalysis (e.g., platinum-based nanozymes), their precision in trajectory control within the complex flow fields of the tumor microenvironment still needs improvement. In terms of motion behavior control, individual nanomotors can achieve direction reversal through surface wettability regulation (e.g., hydrophilic/hydrophobic transitions),¹⁰⁷ while swarms can self-assemble into ordered structures via hydrodynamic interactions (e.g., tumbling motion under different magnetic field frequencies, morphological transitions from loose vortices to stable swarms).¹⁰⁸ However, such behavioral stability is easily disturbed by the tumor microenvironment: high interstitial fluid pressure, abnormal vascular distribution, and dense stromal fibers in tumor tissues not only cause attenuation of external field signals or disruption of chemical gradients but also alter the interaction between motors and surrounding media through hydrodynamic effects. For instance, the front-end traction flow field of hydrophilic motors or the rear-end propulsion flow field of hydrophobic motors¹⁰⁷ undergoes distortion in high-viscosity interstitial fluid, increasing directional motion errors. Specifically, drug-loaded nanomotor swarms have been confirmed to break through the blood laminar flow barrier by forming vortical flows,¹⁰⁸ demonstrating potential for active drug delivery in blood flow environments. Meanwhile, magnetically driven swarms also face threats to the stability of their self-assembled structures due to increased blood flow shear stress when passing through narrow vascular segments, which provides a direction for optimizing the motion performance of swarms in complex vascular environments. Additionally, the high viscosity of tumor interstitial fluid significantly reduces motor motion efficiency. Although this can be improved through active regulation strategies—such as photomagnetic coupling-driven nanomotors incorporating near-infrared II (NIR-II) lasers to reduce viscosity, with enhanced penetration capability due to fluid disturbance at their tips,¹⁰⁹ or the design of viscosity-responsive driving surfaces (e.g., pH-triggered hydrophilic–hydrophobic transitions to adjust speed)—the matching between rotational dynamics and local fluid resistance in complex flow fields remains difficult to precisely control. Future research should integrate biomimetic chemotactic mechanisms (e.g., simulating directional migration of leukocytes), multi-field coupling feedback, and refined modeling of fluid-motor interactions to achieve precise manipulation from millimeter-scale tissue localization to subcellular targets, while improving the environmental adaptability of both individual and swarm motion behaviors.

(2) The design bottleneck of long-range transport capability: whether relying on physical driving of external energy (such as magnetic, optical, and ultrasound) or chemical driving of endogenous fuels (such as glucose and urea) in the tumor microenvironment, the directional motion of micro/nanomotors highly relies on sustained energy gradients. However, the energy attenuation of a single device in complex physiological environments within the body is significant (such as low light energy utilization efficiency in deep tumors driven by light, short gradient maintenance time due to chemical driven fuel consumption, and difficulty in achieving long-distance material transport above the centimeter level). Breaking through this limitation requires the construction of modular designs that can be driven in series. For example, the development of relay chemical motors based on enzyme cascade reactions (using urea decomposition products to drive a primary motor, and the generated ammonia triggers a secondary motor), or the construction of a magnetic driven nanocluster coordinated transport network (synchronously regulating group movement trajectories through magnetic fields), to achieve efficient cross scale transport from vascular delivery (millimeter level) to tumor stromal infiltration (micrometer level).

(3) The intelligent response deficiency of complex microenvironments: the dynamic heterogeneity of tumor microenvironments (such as alternating hypoxic and oxygen rich zones, pH fluctuations of 5.5–7.4, and matrix hardness changes of 1–100 kPa) imposes strict requirements on the environmental adaptability of micro/nanomotors. Existing motors mostly respond to a single signal (such as pH only triggering drug release or light only driving), lacking the ability to comprehensively interpret multiple environmental parameters (temperature, metabolite concentration, and immune signals), resulting in low synergistic efficiency of “motion-release-therapy” within tumors. The development of intelligent micro/nanomotors requires the integration of sensing and decision-making functions, such as modifying DNA aptamers on the surface of the motor to identify tumor markers, and combining machine learning algorithms to adjust the driving strategy in real time. When encountering high hardness matrices, it switches to bubble driving to enhance penetration, and accelerates drug release when entering acidic regions.

(4) Long-term biosafety: researchers have used in vitro testing methods to evaluate the biocompatibility of micro/nanomotors, such as cytotoxicity assays, hemolysis rate tests, and some in vivo animal experiments. However, before translating to clinical applications, further long-term systematic evaluation using larger animals (such as pigs, monkeys, etc.) may be required. The long-term biosafety of micro/nanomotors with different driving mechanisms also needs more detailed assessment. For example, physical and chemically driven micro/nanomotors mostly require chemical synthesis, necessitating evaluation of their degradation cycles, degradation products, and in vivo toxicity. For biohybrid-driven micro/nanomotors, further assessment of acute biosafety is needed, including immune responses upon in vivo administration and their final fate after task completion, to confirm the absence of side effects.

The breakthrough of these limitations not only relies on the advancement of motor material properties, preparation, and characterization processes, but also requires the integration of analysis of the tumor microenvironment and artificial intelligence control algorithms to promote the transition of nanomotors from “experimental prototypes” to “precision treatment carriers”.

Author contributions

Qi Guo: writing original draft. Hong Wang: investigating and collecting the reviews. Hongyuan Hao: collecting and summarizing the figures. Cuimiao Zhang: reviewing and editing. Xing-Jie Liang: providing valuable insights into the interpretation of results and enhancing the scientific rigor of the content. Dandan Liu: funding acquisition, conceiving the review topic, designing the overall framework, and supervising the writing process.

Conflicts of interest

The authors declare no conflict of interest, financial or otherwise.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

Acknowledgements

This study was supported by the National Natural Science Foundation of China (32471460), the Science Fund for Creative Research Groups of Nature Science Foundation of Hebei Province (B2021201038), the Natural Science Foundation of Hebei province (B2023201108), the Hebei Province Higher Education Science and Technology Research Project (ZD2022075), the Central Government-Guided Special Funds for Local Scientific and Technological Development (226Z2603G), the National High-End Foreign Expert Recruitment Plan (G2022003007L), the Research and Innovation Team of Hebei University (IT2023C06 and IT2023A01), and the Hebei Province Innovation Capability Enhancement Plan Project (22567632H).

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