External physical field‐driven nanocatalytic cancer therapy

Abstract

Recently, variable nanocatalysts have provided novel, highly selective, minimally invasive strategies driven by external physical fields for cancer therapy. In the catalytic reaction, less toxic or nontoxic substances can be in situ converted into toxic agents for cancer suppression. In this review, we systematically summarize the catalytic cancer therapy based on different types of external physical fields, including light, ultrasound, electricity, temperature, X‐ray, magnetic field, and microwave. The properties, mechanisms, and advantages of the corresponding external physical fields in cancer therapy are also introduced. Importantly, considering the rapid development of catalytic nanomedicine, the research progress of catalytic cancer therapy driven by external physical fields is discussed. Finally, the remaining challenges and outlooks that catalytic cancer therapy faced are also outlined. We believe that the emerging external physical fields‐driven nanocatalytic cancer therapy will provide a new avenue for cancer treatment.

INTRODUCTION

Cancer is still the leading cause of death globally, second only to cardiovascular disease. This frustrating result may relate to inadequate early diagnosis and unsatisfactory cancer treatments. Traditional cancer treatments, including surgery, chemical therapy, and radiotherapy have some shortages to some extent. For example, highly invasive surgery cannot eliminate all cancer at the same time. Chemical therapy and radiotherapy have severe side effects and can damage the immune system. Therefore, the development of new therapeutic treatments with low toxicity and high efficiency are emerging. Interestingly, the promising catalytic nanomedicine supplies a potential solution for the challenges.

Currently, numbers of research studies have provided rational strategies for designing nanomaterials with precise size and morphology, suitable structure, and stable catalytic performance, which can meet the therapeutic requirement with customization. What's more, in cancer theranostics, the use of nanomaterials is advanced for their unique properties such as large specific surface area, adjustable surface, high drug loading ability, and unique catalytic capability. Based on their superiority, nanomaterials with catalytic ability is a promising choice in cancer treatments and this treatment is named as nanocatalytic cancer therapy. In nanocatalytic cancer therapy, nanomaterials can convert substances as therapeutic agents by various catalytic reactions under endogenous conditions (e.g., low pH and high-level hydrogen peroxide [H₂O₂]) or external physical fields (light, ultrasound, electricity, temperature, X-ray, magnetic field, and microwave). Compared to endogenous conditions, it can achieve high spatiotemporal controllability and adjustable catalytic performance supplied by external physical fields as remote or wireless energy. In addition, the nanocatalytic cancer therapy under external physical fields shows high selectivity, minimal invasiveness, and negligible side effects when compared with traditional cancer therapies, which inspires researchers to design and synthesize nanomaterials with high catalytic performance under external physical fields for cancer treatments.

Herein, the different types of the external physical field, including light, ultrasound, electricity, temperature, X-ray, magnetic field, and microwave, based catalytic cancer therapies were summarized to highlight the research progress (Scheme ). The research studies of well-known photodynamic therapy (PDT) and sonodynamic therapy (SDT) have been intensively researched and discovered for their mechanisms and catalytic pathway, which will be discussed in detail in the corresponding section. On the other hand, some catalytic therapies, such as that irradiated by magnetic field and electricity are in their infancy. Hence, the properties and the prospect need to be focused.

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Finally, we discussed the remaining challenges and outlooks for catalytic cancer therapy. We believe that the emerging external physical field-driven nanocatalytic cancer therapy will change the undesirable status of cancer treatment.

THE NANOCATALYTIC THERAPY DRIVEN BY LIGHT

Light has been applied as a therapeutic technique for thousands of years. In recent years, phototherapy has developed rapidly due to its noninvasive nature and high selective killing efficiency. According to the mechanism, traditional phototherapy is divided into photothermal therapy (PTT) and PDT. The working principle of PTT is mainly based on the conversion between light and thermal energy, which will not be discussed in this review. In PDT, there are three key components: photosensitizers, oxygen (O₂), and light with specific wavelengths. As shown in Figure , under the stimulation of external light, the photosensitizer is activated and its electrons jump from the ground state to the excited state. After intersystem crossing (ISC), reactive oxygen species (ROS), such as H₂O₂, hydroxyl radicals (•OH), superoxide radical (•O₂⁻), or singlet oxygen (¹O₂), are generated through two reaction pathways (type I and type II PDT). These ROS are further used in organisms to treat the disease by inducing apoptosis, pyroptosis or necrosis, activating immunity, or damaging blood vessels.

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Although PDT has advantages over conventional treatments, there are still many limitations. According to the mechanism, the development of PDT is influenced by the following factors: (1) Limitations of photosensitizers: The currently available photosensitizers have a low ROS yield and short lifetime of ROS; organic photosensitizers possess poor stability and inorganic photosensitizers are difficult for metabolism. (2) Limitations of the light source: The shallow penetration depth of the light makes it difficult to achieve a deep tumor cure. (3) O₂ limitation: The hypoxic microenvironment at the tumor site limits the generation of free radicals. (4) Other factors: In the PDT, the targeting ability and potential biosafety of photosensitizers should also be considered.

In recent years, a series of strategies has been gradually developed to improve the efficacy of PDT by solving these limitations. Through the rational design of nanomaterials, the researchers have further improved the yield and lifetime of triplet exciton, elevated ISC ability, enhanced energy transfer efficiency, etc., and realized the efficient generation of ROS. Zhao et al. developed heavy-atom-free cyanine dyes to generate ROS under near-infrared light (NIR) based on the spin-orbit charge-transfer ISC (SOCT-ISC) mechanism, which enhances ISC and extends the excited state lifetime by introducing a spatially bulky and electron-rich steric structure (Figure ). To improve the intrinsic defects of photosensitizers, the solubility and stability of small organic molecules are improved by developing new stable photosensitizers, organic/inorganic hybrid strategies, nanocarrier strategies, and other strategies. Besides, degradable photosensitizers are also developed to improve biosafety. To address the problem of difficult metabolism of carbon nanomaterials, our team designed a degradable carbon-silica nanocomposite (CSN) with immunoadjuvant properties and photodynamic performance (Figure ). It was then validated on the patient-derived xenograft model to promote its clinical application. To solve the problem of shallow penetration of the light source in PDT, NIR, NIR-II, NIR-III, and other light sources with long wavelength areas were further expanded to increase the penetration depth. Tao's team took thulium oxide (Tm₂O₃) as an example and believed that broadband sources excitation can commendably meet the demands of different applications (Figure ). In addition, Ding et al. constructed a self-activatable and self-luminous extracellular vesicle delivery system, to realize the chemiexcited PDT without external excitation light (Figure ). Overcoming tumor hypoxia limitation has been one of the hot spots in PDT. Several different strategies have been developed to solve that, such as increasing the proportion of type I PDT, depleting endogenous H₂O₂ to produce O₂ (Figure ), and catalyzing H₂O to produce O₂ (Figure ), etc. Luo et al. achieved PDT enhancement by reducing the size of the photosensitizer, thus increasing the contact probability of the photosensitizer with O₂ and also promoting the diffusion of ROS (Figure ). Zhao et al. and Guo et al. further improved the ability of photosensitizers to target organelles through a rational design. On the other hand, PDT combined with nanozymes and chemokinetic therapies can greatly improve efficacy. Liu et al. constructed a H₂O₂/O₂ self-supplying nanoagent by loading calcium peroxide (CaO₂) and indocyanine green on manganese silicates (MSNs) and finally encapsulating them with lauric acid. The MSNs reacted with glutathione (GSH) and mediated the Fenton-like effect of manganese ions, the CaO₂ reaction generated O₂ and H₂O₂ further enhancing the efficacy of PDT and chemodynamic therapy (CDT).

PDT has gradually advanced clinically in recent years and has broad prospects in the field of tumor treatment. Compared to the other types of catalytic therapies described subsequently, the development of PDT has played a leading role in recent years. However, there is still a long way to go before it can be further promoted clinically. What's more, it is necessary to further develop efficient photosensitizers, improve photon utilization, biological safety, and targeting. Although there are many strategies to address the limitations of PDT, its actual clinical efficacy still needs further validation.

THE NANOCATALYTIC THERAPY DRIVEN BY ULTRASOUND

Similar to PDT, SDT is a novel and noninvasive treatment modality that generates ROS with the help of low-intensity ultrasound to excite sonosensitizers. Compared with light, ultrasound has stronger tissue penetration ability to deal with deep tissue lesions, and therefore, SDT is often used as an alternative to PDT for deep-seated solid tumors.

Since the SDT was found, researchers have gradually provided mechanisms, such as sonoluminescence, piezoelectric effect, ultrasonic cavitation effect, sonomechanical damage, and pyrolysis, through the research studies based on the process of bubble collapse and energy release caused by inertial cavitation of ultrasound in liquids (Figure ). But some of these mechanisms are still unverifiable due to the limitation of accuracy and detection capability of the equipment. In the sonoluminescence-mediated nanocatalytic therapy, the rupture of the cavitation bubble emits light, which further excites the sonosensitizer to generate electron-hole pairs to form •OH, •O₂⁻, and other ROS on the surface of the sonosensitizer. The proponents generally believed that in the ultrasonic cavitation mechanism, the high temperature and pressure generated by the bubble rupture will evenly split the water molecules or decompose a part of the sonosensitizer to generate ROS, and the presence of nanoparticles will further stabilize the cavitation nucleus to enhance the process. Piezoelectric effects based on ultrasound triggering have also been proposed in recent years, where piezoelectric nanomaterials undergo force deformation, polarization, and further reaction to generate ROS. In addition, the built-in electric field generated by polarization causes energy band tilting, which facilitates the redox reaction.

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Although SDT can theoretically replace PDT for the treatment of deep tumors. However, the efficacy of SDT is still far from the desired effect due to the low yield of ROS, the defective nature of sonosensitizers, and the complexity of tumor microenvironment (TME). Based on this, researchers have also proposed different strategies to achieve efficient cancer treatment under ultrasound irradiation. The acoustic power performance can be effectively enhanced through the rational design of modulated sonosensitizers. (1) Constructing vacancies in the sonosensitizers to inhibit electron-hole recombination. Yang et al. using photolithography, introduced O₂ vacancies in the BiVO₄ sonosensitizer, enhancing charge separation and alleviating tumor O₂ deprivation by decomposing H₂O to produce O₂ (Figure ). (2) Construction of heterostructures and modulation of the energy band structures to enhance ROS generation. Kang et al. prepared a two-dimensional interplanar Z-type heterojunction (FeOCl/FeOOH NSs), the presence of the built-in electric field enhanced the charge transfer, while the catalytically generated O₂ further combines with valence band electrons to generate H₂O₂, enhancing the Fenton reaction of iron ions (Figure ). (3) Adjusting the hydrophobicity and morphological structure of the sonosensitizers can effectively enhance the cavitation effect. The metal–organic framework-derived mesoporous carbon nanostructure (PMCS) constructed by our group exhibited a stronger cavitation effect due to its porous structure and high specific surface area. For the first time, bubbles and microjets formed by the nanomaterial-assisted cavitation process were captured by a high-speed camera (Figure ). In addition, we further revealed the enhanced mechanism of the cavitation effect by changing the wettability of the MSNs surface and used it for ultrasonic thrombolysis treatment (Figure ). (4) Combining CDT such as the depletion of endogenous GSH, synergistic with Fenton and Fenton-like reactions, and enhancement of oxidative stress, etc. Zhao et al. constructed Cu/CaCO₃@Ce6 nanoparticles, where the release of Cu ions depletes GSH and further generates •OH through Fenton-like reactions to achieve a synergistic treatment of CDT and SDT. (5) Synergistic gas therapy, such as O₂, CO₂, NO, etc., to achieve overcoming tumor hypoxia, enhancing cavitation effect, and enabling imaging functions. Li et al. prepared sonosensitizer titanium sulfide nanosheets (TiS_X NSs) that can release hydrogen sulfide gas, which not only promoted apoptosis of cancer cells but also activated the immune system to inhibit lung metastasis, and TiS_X NSs gradually formed sulfur vacancies and partially oxidized into TiO_X, which enhanced the sonodynamic effects (Figure ).

SDT has a broad development potential in the field of nanomedicine because of its noninvasiveness and great penetrating capacity, offering novel methods for clinical therapy. However, the uncertain therapeutic mechanism still limits the development of SDT. The actual mechanism in vivo still needs more quantification, characterization, and evaluation. Moreover, there are no standardized parameters and models currently available, which hinders the progress of SDT technology. In addition, the design of safe and efficient sonosensitizers is particularly important.

THE NANOCATALYTIC THERAPY DRIVEN BY ELECTRICITY

Electricity has been widely applied in clinical treatment because of its high penetration and controllability. There are two types of electric catalytic therapies that are minimally invasive: electrochemical therapy (EChT) and electrodynamic therapy (EDT). In EChT, low-voltage direct current is passed to the tumor through electrodes that then induce drastic pH changes and substance generation such as ROS and hydrogen (H₂). Qi et al. reported a H₂ generation EChT (H₂-EChT) by acupuncture. The two acupuncture electrodes are punctured into the solid tumor and direct current (∼3 V) is passed driving the electrochemical H₂ generation in an acidic TME (Figure ). The result shows that the H₂ concentration is positively related to an acidic condition and the treated group has a good suppression effect (Figure ). EDT utilizes alternating current electricity to drive the catalytic reaction on nanomaterials to convert substances into active agents. Chen et al. synthesized Pt/Cu alloy nanoparticle (PtCu₃-PEG) and integrated chloride ion transporter for enhancing EDT (Figure ). Under an electric field, the PtCu₃-PEG showed a high-level ROS generation, which was evaluated by ultraviolet-visible spectra and electron spin resonance spectra (ESR). Because chloride ion assisted the O–H band breaking into •OH by the Faraday cage effect under the electric field. The chloride ion transporter was applied to enhance the intracellular chloride ion to improve the EDT effect (Figure ). They also emphasized that using alternating current electricity in EDT can avoid drastic pH changes. Up to now, numerous nanomaterials, such as Pt nanoparticles, manganese cluster nanoparticle, and zeolite imidazole framework have been utilized in EDT or EDT-based comprehensive therapy. Undoubtedly, EDT is a potential cancer therapy with high selectivity and minimal invasiveness. Compared with the therapy driven by other physical fields, electricity is beneficial to directly decompose water into ROS without the limitation of O₂ or H₂O₂ concentration. At present, research studies only focus on ROS generation for cancer apoptosis by EDT. However, with similar catalytic behavior, electricity has been applied for synthesizing various substances such as CO, H₂, and H₂O₂. It means that customizable agents can also be rationally synthesized in the tumor site to achieve a multiple effect driven by electricity. In fact, there are some challenges that EDT and EChT are faced. For example, both of them need to insert electrodes into the tumor, which is unsuitable for tiny or deep tumors.

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THE NANOCATALYTIC THERAPY DRIVEN BY TEMPERATURE

Temperature is one of the most important factors that determine the vitality and function of biological systems. Although changes in temperature are sometimes harmful for the organism, heat therapy can achieve the healing of some diseases through proper design and utilization. Thermo-catalytic therapy is an emerging therapy developed in recent years. In the process of thermal catalysis, high temperature provides the thermodynamically required activation energy for the reaction, thus promoting the production of ROS species.

Thermo-catalytic therapy is currently divided into two forms, that is, thermodynamic therapy (TDT) and pyroelectric-dynamic therapy (PEDT). TDT uses thermal effects to accelerate chemical reactions and activate free radical prodrugs to produce cytotoxic free radicals. The reported free radical prodrugs are currently mainly based on 2,2'-azobis[2-(2-imidazolin-2-yl) propane] dihydrochloride (AIPH). AIPH is a water-soluble thermally unstable molecule that decomposes under heat to generate alkyl radicals, which can overcome the tumor O₂-depleted microenvironment for treatment. On the other hand, PEDT realizes the conversion among thermal energy, electrical energy, and chemical energy by utilizing the thermoelectric effect of thermoelectric materials in combination with electrochemical redox reactions. The thermoelectric effect refers to the spontaneous polarization of certain polar materials in the presence of temperature fluctuations, which in turn produces a change in the electric potential. At constant temperature (dT/dt = 0), the built-in electric field and depolarization field formed by the thermoelectric material reach equilibrium and no electric potential is generated. However, when the temperature fluctuates (dT/dt ≠ 0), the balance is broken, positive and negative charges are generated on the surface of the materials, and the reaction generates ROS. In addition, periodic temperature changes are often required to continuously trigger the thermoelectric effect to sustain the reaction to generate ROS. Because of the specificity of the thermoelectric effect, it has been gradually used in recent years in fields such as H₂ production, dye decomposition, sterilization, and disease treatment.

No matter which mechanism of thermo-catalytic therapy, the heat source is the primary prerequisite. Due to the complexity of disease treatment, traditional heat radiation and heat conduction are less effective, while heat generation through light, microwave, electric field, and magnetic field can achieve localized and deep-seated efficient heat therapy. At present, the main types of thermo-catalytic therapy are photo-thermodynamic therapy (P-TDT) and electro-thermodynamic therapy (E-TDT). In P-TDT, the photo-thermal energy conversion is achieved through photothermal agents, such as gold nanorods, TiO₂, polydopamine nanomaterials, conjugated polymers, etc. Xiang et al. encapsulated AIPH molecules within Nb₂C@mSiO₂ to achieve NIR-II-triggered O₂-independent TDT (Figure ). E-TDT uses electrothermal materials to generate heat through an applied electric field. To meet the precise temperature control, Liu et al. used the chemotherapeutic drug gossypolone (Gn) as a carrier and superimposed it with AIPH to form AIPH-Gn MSC NPs (APGn NPs). A designed micro-electrothermal needle (MEN) system with a controlled heating section was used to treat tumors through electrothermal–thermodynamic–chemo trimodal combination therapy (Figure ). In addition, studies have shown that free radicals generated by TDT can also activate immune responses. On the other hand, some novel free radical precursors have been developed to enrich the TDT system. For PEDT, the material is required to have a thermoelectric effect and temperature fluctuations to operate below the Curie temperature (T_C). Most of the thermoelectric materials are semiconductor materials, and the catalytic properties of which are related to the energy band structure. Wang et al. constructed Bi₁₃S₁₈I₂ nanorods with high photothermal conversion and thermoelectric properties, generating ROS that consume heat–shock proteins (HSPs) for enhanced tumor hyperthermia (Figure ). He et al. grew the thermoelectric material CdS in situ on an ultrathin Nb₂C nanosheet (MXene) and used the photothermal effect of MXene to activate the catalytic decomposition of H₂O by CdS to generate O₂ and •OH, which reduced tumor interstitial pressure (TIP) to enhance tumor penetration and effectively inhibited tumor growth (Figure ). The thermoelectric catalytic performance can be further enhanced by constructing heterojunctions. In addition, because of the properties of thermoelectric materials, using the thermoelectric cooler to reduce the temperature, Wu et al. used black phosphorus (BP) nanosheets as catalysts to achieve cold-catalytic therapy (Figure ). In addition, by simulating oral temperature fluctuations, Wang et al. proposed a tooth-whitening strategy based on the thermoelectric catalytic effect using barium titanate (BaTiO₃) nanowires as a model (Figure ).

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Thermo-catalytic therapy has gained significant interest recently, but it is still in its infancy and has some restrictions and issues in equipment and catalysts: (1) The thermo-catalytic therapy based on the thermoelectric effect currently has poor temperature control, leading to a relatively low catalytic efficiency; (2) New thermo-catalytic nanomaterials need to be developed to enrich the entire system; (3) Because thermo-catalytic therapy is carried out through multiple heating modalities, it can be more convenient to enhance therapeutic efficacy through combined strategies. The future development of thermo-catalytic therapy still needs more efforts.

THE NANOCATALYTIC THERAPY DRIVEN BY X-RAY

X-ray is a kind of electromagnetic wave with high energy (12–120 eV) and short wavelength (10–100 nm). Based on the deep penetration of X-ray, radiotherapy has been developed as the main cancer therapy with a high requirement for the X-ray dose, which has bad therapeutic efficiency with low radiation dose or serious side effects for normal tissues with high radiation dose. Considering those problems, radioactive catalytic therapy with high selectivity and efficiency was developed for cancer treatments by radiosensitizers under X-ray irradiation. There are two types of catalytic mechanisms of radiosensitizers. In the first mechanism, radiosensitizers containing high atomic number (Z) can strongly absorb X-ray to release electrons for ROS generation, because the photoelectric effect of X-ray is positively related to (Z/E)³, where E is the energy of incident X-ray (Figure ). At present, the popular high-Z elements for X-ray-dependent catalytic cancer therapy include Au, Bi, W, rare Earth elements, etc. Another mechanism relates to semiconductors that receive X-ray then excite electrons into the conduction band and leave holes in the valence band. The electron-hole pairs are further reacted with O₂, water, or other O₂-containing substances to generate ROS. For example, Zhao et al. developed the Au-Bi₂S₃ metal–semiconductor heterostructure (Au-Bi₂S₃ HNSCs) as a radiosensitizer for catalyzing intracellular H₂O₂ under X-ray irradiation to improve therapeutic efficacy in hypoxic tumor. The Au-Bi₂S₃ HNSCs strongly deposit X-ray as high-energy electrons and low-energy electron-hole pairs. The low-energy electron-hole pairs can be rapidly separated by the Schottky barrier and decompose H₂O₂ into •OH. They also prove that the Au-Bi₂S₃ HNSCs have better catalytic performance than Bi₂S₃ nanorods or the mixture of Bi₂S₃ nanorods and Au nanocrystals (Figure ).

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To achieve a suitable radio-catalytic therapy, there are some strategies for improving the therapeutic efficiency. (1) Improving O₂ concentration in the tumor: Generally, radioactive catalytic therapy is highly dependent on O₂. However, the TME is hypoxic, which restrains the therapeutic effect, especially in deep tumors. To improve the O₂ concentration, it is efficient to transport O₂ using nanocarriers. Clement et al. designed an O₂ carrier based on perfluorooctylbromide, to improve the therapeutic effect of verteporfin radiosensitizer under X-ray irradiation (Figure ). They simulated hypoxic conditions in PANC-1 cells and found an excellent treatment effect after applying the material. (2) Combining semiconductor and materials with high-Z element: Considering the strong X-ray deposition of high-Z element and the easily induced electron-hole pair in the semiconductor, the combination of these two materials can improve the X-ray utilization rate. In addition, the heterojunction of combinations can reduce the recombination of electron-hole pair to increase ROS generation. Wang et al. synthesize bovine serum albumin-coated BiOI@Bi₂S₃ heterojunction (SHNPs). The SHNPs containing high-Z elements (Bi and I) show strong X-ray attenuation capability and offer an extra approach for ROS generation by electron-hole pair under X-ray irradiation (Figure ).

Unquestionably, radio-catalytic therapy is still in the infancy stage, which needs more effort to discover the concrete mechanism and develop functional nanomaterials for enhancing the therapeutic effect. What's more, there are still a lot of challenges for the clinical translation of radiosensitizers and rational design of nanoparticles.

THE NANOCATALYTIC THERAPY DRIVEN BY MAGNETIC FIELD

The magnetic field is noninvasive or causes minimal damage to normal tissues and possesses higher penetration than photo and ultrasound. In a long period, the magnetic field was only recognized as catalytic reaction boosters to enhance the catalytic reaction. Currently, the magnetic field has been applied as a direct trigger of the catalytic reaction. Magnetic catalytic reaction is based on the magnetoelectric effect of multiferroic and magnetoelectric composites. With regard to magnetic fields, the magnetic component transfers the magnetostrictive strain to the ferroelectric component to induce the generation of electrons and holes. The magnetic catalytic cancer therapy is currently in its initial stage, Shi et al. firstly reported the CoFe₂O₄–BiFeO₃ (CFO–BFO) core–shell nanoparticle that acted as a magnetic catalyst for cancer treatment in 2021. They synthesized CFO–BFO core–shell nanoparticles with two steps. The CoFe₂O₄ was initially synthesized using hydrothermal methods and BiFeO₃ was shelled on the CoFe₂O₄ through the sol-gel route. The CoFe₂O₄ undergoes magnetostriction under an alternating magnetic field to induce polarization on the surface of CFO–BFO core–shell nanoparticles. Subsequently, ROS including •OH and •O₂⁻ were generated by the piezoelectric effect of BiFeO₃. CFO–BFO core–shell nanoparticle possessed ROS generation ability thereby inducing the death of cancer cells and the ablation of tumor (Figure ). Though the history of magnetic catalysis is short, it has been applied for various applications such as organic degradation, hydrogen evolution, biofilm elimination, and cancer therapy. However, all of the applications we have known are based on CFO–BFO core–shell nanoparticles, which obviously cannot meet the requirements for therapeutic treatment. As a promising field, the types of magnetoelectric catalysts should be developed to achieve a diverse set of applications. Generally, single-phase materials such as Cr₂O₃ and Y₃Fe₅O₁₂ show the magnetoelectric effect at low temperature, which is inconvenient in practical applications. Compared to single-phase materials, composites containing ferromagnetic and piezoelectric materials show a higher magnetoelectric effect at room temperature, which shows the potential in the biomedicine field. The main three types of ferromagnetic materials are nickel-based alloy, iron-based alloy, and ferrite, which have been reported in biomedicine. In addition, barium titanate and polyvinylidene fluoride are popular and have low biological toxicity among the many different types of piezoelectric materials. Combining these ferromagnetic and piezoelectric materials, the magnetoelectric coupling can be improved to achieve an effective and promising magneto-catalytic therapy.

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THE NANOCATALYTIC THERAPY DRIVEN BY MICROWAVE

Microwave is a kind of electromagnetic wave with a long wavelength (0.01–1 m) and high frequency (0.3–300 GHz). Based on the high penetration ability and minimal side effects, the microwave is applied in clinical practice. For medical purposes, the frequency is usually applied at 2.45 MHz. Microwave can directly generate ROS by microwave sensitizers under microwave irradiation, which is named as microwave dynamic therapy (MDT). In most cases, MDT is combined with microwave thermal therapy under the microwave sensitizers such as liquid metals (LM). Yu et al. utilized liquid metal eutectic gallium indium to generate ROS under microwave irradiation to achieve a combination therapy with CDT (Figure ). Wu et al. synthesized eutectic gallium indium alloy to generate •OH and •O₂⁻ under microwave irradiation to achieve a combination of dynamic and thermal therapy (Figure ). The generation mechanism of •OH and •O₂⁻ is that the electron passes from gallium to O₂ and water under microwave irradiation and convert them to •OH and •O₂⁻, respectively. Nanocrystal is another kind of microwave sensitizer. Tang et al. synthesized Cu₂ZnSnS₄ nanocrystals (CZTS NCs) for ¹O₂ generation to induce cancer apoptosis. The CZTS NCs also show a significant temperature increase because of the high microwave absorption of Sn and Cu elements (Figure ). Recently, metal–organic framework (MOF) was also discovered as a microwave sensitizer for MDT. Meng et al. synthesized an MOF constituted by Bi³⁺, Mn²⁺, and meso-tetra (4-carboxyphenyl) porphine. The MOF showed a high ¹O₂-producing ability owing to the separation of electron-hole pairs in the system containing Mn under microwave irradiation.

Although many studies have been conducted, there is still a long way that MDT needs to go: (1) The mechanism of MDT and the catalytic behavior in vivo should be clarified. (2) The types of microwave sensitizers should be expanded and the law of microwave sensitizers should be clarified.

CONCLUSION AND PERSPECTIVES

Due to the unsatisfactory therapeutic efficiency and severe side effects of traditional cancer therapy, researchers are focusing on developing novel cancer therapy to meet the requirements of the therapeutic application. Rapidly developed nanocatalytic cancer therapy provides an excellent choice to solve these problems. Driven by the external physical field, the nanocatalytic cancer therapy shows minimal invasiveness, negligible side effects, and spatiotemporal controllability to convert nontoxic or slightly toxic substances into therapeutic agents to inhibit cancer (Table ). Recently, external physical field-driven nanocatalytic therapies have achieved remarkable progress and increasingly attract attention for the strategies and the ideal. Undoubtedly, this therapy will play an important role in cancer treatment from bench to bedside in future, but some strategies should be formulated to solve challenges before clinical use:

• 1)

  High catalytic performance: Though most of the research studies show satisfactory tumor suppression in an animal model under an external physical field, the high catalytic performance is still the pursuit to meet an efficient cancer therapy. High catalytic performance means that low dosage of catalytic nanomedicine needs to achieve a suitable therapeutic efficacy. To improve the catalytic performance, it needs a rational design on the structure and composition of catalytic nanomedicine.

• 2)

  Catalytic behaviors in vivo: Due to the complicated in vivo microenvironment, including pH, enzyme, and oxidative stress, the catalytic behaviors of nanomaterials may not follow the experimental catalytic mechanism. To precisely control the catalytic reaction of catalytic nanomedicine in tumors under external physical fields, it is urgent to confirm the possible catalytic pathway and mechanism. For this target, new techniques such as in situ characterization techniques and computational stimulation are powerful tools to understand the catalytic process for precise treatment.

• 3)

  Selectivity and accumulation of catalytic nanomedicine: The accurate accumulation of catalytic nanomedicine in a tumor site is a guarantee for cancer therapy with low side effects and high efficiency. In most of the cases, the catalytic nanomedicines accumulated in the tumor site due to the enhanced permeation and retention (EPR) effects. The EPR effect is controversial and the accumulation efficiency of EPR is relatively low. On the other hand, accurate accumulation can reduce the dosage to lower potential toxicity of catalytic nanomedicine. Therefore, novel and effective strategies should be developed to improve accumulation in the tumor site, especially for deep tumors and decrease it in normal tissue to degrade the side effect.

• 4)

  Biocompatibility and biosafety: High biocompatibility and biosafety are the prerequisites of catalytic nanomedicine for clinical translation. Despite the fact that the majority of studies have shown that catalytic nanomedicines have negligible or very low short-term toxicity to healthy tissues, these catalytic nanomedicines are still likely to interact with their biological environment and result in long-term toxicity and adverse reactions, which impede their potential use in biomedical applications. Surface modification can increase the biocompatibility of catalytic nanomedicine, but it will also reduce the number of catalytic active sites and influence the catalytic activity under external physical field. Therefore, the future clinical development of catalytic nanomedicine depends greatly on proper engineering design to enhance biocompatibility and retain high catalytic activity. For clinical translation of catalytic nanomedicines, there are other problems that should be solved. One of the main problems is the difference between the occurrence and development of human and animal diseases. However, most of the research studies of catalytic nanomedicines are focused on their behavior in animal models and the research of their behavior in humans is still in its infancy. The low biodegradability of catalytic nanomedicines also limit the clinical translation. The catalytic nanomedicines that remain in the body may stimulate immune response and damage the human body. To accelerate the transition from basic to clinic, it is necessary to establish a complete clinical evaluation and detection system.

• 5)

  Catalytic reaction type extension: With the rapid development of nanomedicine, higher expectations were endowed to the catalytic therapy to achieve diversified therapy modulation. Apart from ROS generation, nanomedicine driven by external physical fields can catalyze many chemical reactions such as gas generation (H₂, CO, etc.). Gas therapy is an emerging cancer therapy used to kill cancer cells through specific accumulating toxic gases at tumor sites. Using nanomedicine to generate gas in situ can avoid the uncontrollable diffusion, improve permeability, and achieve accurate catalytic therapy. Therefore, extending catalytic therapy types can achieve highly efficient and customized cancer therapy in the future.

• 6)

  Large-scale production: Most of the catalytic nanomedicines are still primarily studied in laboratories. The large-scale production and usage of these catalytic nanomedicines are constrained by the complicated method, difficult scale production, and expensive equipment. In addition, the injected dosages in clinics are significantly higher than those given to small animals in the laboratory which also limited the application. Therefore, it is important to produce low-cost catalytic nanomedicine under mild conditions to meet the clinical requirements.

TABLE 1 The summary of different types of external physical field-driven nanocatalytic therapy.

Physical fields	Represent materials	Parameters	Advantages	Shortages
Light	Porphyrins and their derivatives, carbon dots, Au nanorods, etc.	650 nm, 100 mW cm−2, 15 min 808 nm, 2.0 W cm−2, 5 min 1567 nm, 0.5 W cm−2, 6 min	High tumor destruction selectivity. Noninvasive nature and low side effect. No obvious drug resistance. Mature treatment system, a few PDT have been used for clinical treatment.	The photosensitizers have a low ROS yield and short lifetime of ROS. Light source penetration depth is shallow. O2 limitation. The targeting ability and potential biosafety of photosensitizers.
Ultrasound	Porphyrins and their derivatives, TiO2, MOF, etc.	1 MHz, 1.5 W cm−2, 50% duty cycle, 5 min 1 MHz, 2.5 W cm−2, 50% duty cycle, 5 min 1 MHz, 1.0 W cm−2, 50% duty cycle, 10 min	Noninvasiveness and high selectivity. Compared with light, ultrasound has stronger tissue penetration ability. No obvious drug resistance.	Some mechanisms are still unverifiable. Low efficacy. There are no standardized parameters and models currently available.
Electricity	Pt nanoparticles, manganese cluster nanoparticle, zeolite imidazole framework, etc.	Direct current electricity, 3 V Alternating current electricity, square wave, 10 mHz, 5 mA, 3 min	High controllability and minimal invasiveness. Low cost and surgical simplicity. Directly decompose water into ROS without the limitation of O2 or H2O2 concentration.	Unsuitable for tiny and deep tumors. Low selectivity of EChT. Most of the electric catalysts are nonbiodegradable. There are no standardized parameters and models currently available.
Temperature	AIPH, BaTiO3, CdS, etc.	0.35 V 808 nm, 1.2 W cm−2, 10 min	Noninvasiveness and high selectivity. Wide range of temperature sources.	Low catalytic efficiency. Temperature cannot be precisely controlled. Few available thermo-catalytic nanomaterials. Immature treatment system.
X-ray	Materials with High-Z elements such as Au, Bi, W, etc.; upconversion nanoparticles	0–4 Gy 0–10 Gy 0–15 Gy	Deep penetration. High selectivity. Feasible clinical facilities.	Highly dependent on oxygen. Inefficient energy transformation.
Magnetic field	CoFe2O4	1.6 mT magnetic field	Noninvasive or minimal damage to normal tissues. High penetration.	The types of magnetic field nanosensitizers are limited. There are no standardized parameters and models currently available.
Microwave	Liquid metal, nanocrystal, MOF, etc.	1.8 W cm−2 for 5 min 10 W, 2450 MHz for 1.5 min	1. High penetration ability and minimal side effects.	The mechanism is still unverifiable. The type of microwave nanosensitizers are limited. There are no standardized parameters and models currently available.

Although several critical issues remain, nanocatalytic cancer therapy driven by an external physical field is still highly expected and flourishing. It is anticipated that the effort will supply an encouraging direction for satisfactory cancer therapy.

ACKNOWLEDGMENTS

Q.Y. Wu, and H.Y. Zhang contributed equally to this work. This work was financially supported by the National Natural Science Foundation of China (Nos. U21A2085, 22061130205), the National Key Research and Development Program of China (No. 2021YFC2102900), Fundamental Research Funds for the Central Universities and Research Projects on Biomedical Transformation of China–Japan Friendship Hospital (No. XK2022-08), and the Open Foundation of State Key Laboratory of Organic–Inorganic Composites, Beijing University of Chemical Technology (No. OIC-202201010).

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

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