Perovskite-Type Manganese Vanadate Sonosensitizers with Biodegradability for Enhanced Sonodynamic Therapy of Cancer

Sonodynamic therapy (SDT) has attracted intensive attention, but is still hindered by low sonosensitization and non-biodegradability of the traditional sonosensitizers. Herein, perovskite-type manganese vanadate (MnVO₃) sonosensitizers integrating high reactive oxide species (ROS) production efficiency and appropriate bio-degradability are developed for enhanced SDT. Taking advantage of the intrinsic properties of perovskites such as narrow bandgap and substantial oxygen vacancies, MnVO₃ shows a facile ultrasound (US)-triggered electrons-holes separation and restrained recombination, thus enhancing the ROS quantum yield in SDT. Furthermore, MnVO₃ exhibits a considerable chemodynamic therapy (CDT) effect under the acidic condition probably owing to the presence of manganese and vanadium ions. Due to the presence of high-valent vanadium, MnVO₃ can also eliminate glutathione (GSH) within the tumor microenvironment, which synergistically amplifies the efficacy of SDT and CDT. Importantly, the perovskite structure bestows MnVO₃ with superior biodegradability, which alleviates the long-term presence of residues in metabolic organs after therapeutic actions. Based on these characteristics, US-assisted MnVO₃ achieves an excellent antitumor outcome along with low systemic toxicity. Overall, perovskite-type MnVO₃ may be promising sonosensitizers for highly efficient and safe treatment of cancer. The work attempts to explore the potential utility of perovskites in the design of degradable sonosensitizers.     

压电半导体纳米材料在声动力疗法中的应用进展

随着纳米医学的发展, 利用纳米材料在外源超声波的刺激下催化产生过量的活性氧物种(Reactive Oxygen Species, ROS)以治疗疾病的方法, 被称为声动力疗法(Sonodynamic Therapy, SDT), 已引起人们的广泛关注。目前, 开发可用于SDT的高效声敏剂用于提高ROS产率, 仍然是当前研究和未来临床转化的最大挑战之一。近年来, 得益于压电电子学和压电光电子学的兴起, 基于压电半导体纳米材料的新型声敏剂在SDT中崭露头角, 显示出良好的应用前景。本文从压电半导体的结构出发, 介绍了压电半导体纳米材料应用于SDT的机理研究, 以及利用压电半导体纳米材料作为声敏剂在声动力学癌症治疗及相关抗菌性能方面所取得的研究进展。最后, 本文对该领域存在的问题以及未来的发展趋势进行了展望。     

Recent advances in nanomaterials for sonodynamic therapy

Sonodynamic therapy (SDT), as a novel non-invasive strategy for eliminating tumor, has the advantages of deeper tissue penetration, fewer side effects, and better patient compliance, compared with photodynamic therapy (PDT). In SDT, ultrasound was used to activate sonosensitizer to produce cytotoxic reactive oxygen species (ROS), induce the collapse of vacuoles in solution, and bring about irreversible damage to cancer cells. In recent years, much effort has been devoted to developing highly efficient sonosensitizers which can efficiently generate ROS. However, the traditional organic sonosensitizers, such as porphyrins, hypericin, and curcumins, suffer from complex synthesis, poor water solubility, and low tumor targeting efficacy which limit the benefits of SDT. In contrast, inorganic sonosensitizers show good in vivo stability, controllable physicochemical properties, ease of achieving multifunctionality, and high tumor targeting, which greatly expanded their application in SDT. In this review, we systematically summarize the nanomaterials which act as the carrier of molecular sonosensitizers, and directly produce ROS under ultrasound. Moreover, the prospects of inorganic nanomaterials for SDT application are also discussed.

     

Ultrasmall Oxygen‐Deficient Bimetallic Oxide MnWOX Nanoparticles for Depletion of Endogenous GSH and Enhanced Sonodynamic Cancer Therapy

Sonodynamic therapy (SDT) triggered by ultrasound (US) has attracted increasing attention owing to its abilities to overcome critical limitations including low tissue‐penetration depth and phototoxicity in photodynamic therapy. Herein, the design of a new type of sonosensitizer is revealed, namely, ultrasmall oxygen‐deficient bimetallic oxide MnWO_X nanoparticles, for multimodal imaging‐guided enhanced SDT against cancer. As‐made MnWO_X nanoparticles with poly(ethylene glycol) (PEG) modification show high physiological stability and biocompatibility. Interestingly, such MnWO_X‐PEG nanoparticles exhibit highly efficient US‐triggered production of ¹O₂ and ?OH, higher than that of previously reported sonosensitizers (e.g., protoporphyrin IX and titanium dioxide), because the oxygen‐deficient structure of MnWO_X serves as an electron trap site to prevent electron–hole recombination. The glutathione depletion capability of MnWO_X‐PEG can also further favor SDT‐triggered cancer cell killing. With efficient tumor homing as illustrated by computer tomography and magnetic resonance imaging, MnWO_X‐PEG enables effective destruction of mouse tumors under US stimulation. After accomplishing its therapeutic functions, MnWO_X‐PEG can be metabolized by the mouse body without any long‐term toxicity. Herein, a new type of sono‐sensitizing agent with high SDT efficacy, multimodal imaging functions, and rapid clearance is presented, an agent which is promising for noninvasive SDT cancer treatment.     

Custom-Made Piezoelectric Solid Solution Material for Cancer Therapy

Piezoelectric material-mediated sonodynamic therapy (SDT) has received considerable research interest in cancer therapy. However, the simple applications of conventional piezoelectric materials do not realize the full potential of piezoelectric materials in medicine. Therefore, the energy band structure of a piezoelectric material is modulated in this study to meet the actual requirement for cancer treatment. Herein, an elaborate PEGylated piezoelectric solid solution 0.7BiFeO₃-0.3BaTiO₃ nanoparticles (P-BF-BT NPs) is synthesized, and the resultant particles achieve excellent piezoelectric properties and their band structure is tuned via band engineering. The tuned band structure of P-BF-BT NPs is energetically favorable for the synchronous production of superoxide radicals (•O₂⁻) and oxygen (O₂) self-supply via water splitting by the piezoelectric effect. Besides, the P-BF-BT NPs can initiate the Fenton reaction to generate hydroxyl radical (•OH), and thus, chemodynamic therapy (CDT) can be augmented by ultrasound. Detailed in vitro and in vivo research has verified the promising effects of multimodal imaging-guided P-BF-BT NP-mediated synergistic SDT/CDT by the piezo-Fenton process in hypoxic tumor elimination, accompanied by high therapeutic biosafety. The current demonstrates a novel strategy for designing and synthesizing “custom-made” piezoelectric materials for cancer therapy in the future.     

Micro/Nanoparticle‐Augmented Sonodynamic Therapy (SDT): Breaking the Depth Shallow of Photoactivation

The fast development of photoactivation for cancer treatment provides an efficient photo‐therapeutic strategy for cancer treatment, but traditional photodynamic or photothermal therapy suffers from the critical issue of low in vivo penetration depth of tissues. As a non‐invasive therapeutic modality, sonodynamic therapy (SDT) can break the depth barrier of photoactivation because ultrasound has an intrinsically high tissue‐penetration performance. Micro/nanoparticles can efficiently augment the SDT efficiency based on nanobiotechnology. The state‐of‐art of the representative achievements on micro/nanoparticle‐enhanced SDT is summarized, and specific functions of micro/nanoparticles for SDT are discussed, from the different viewpoints of ultrasound medicine, material science and nanobiotechnology. Emphasis is put on the relationship of structure/composition‐SDT performance of micro/nanoparticle‐based sonosensitizers. Three types of micro/nanoparticle‐augmented SDT are discussed, including organic and inorganic sonosensitizers and micro/nanoparticle‐based but sonosensitizer‐free strategies to enhance the SDT outcome. SDT‐based synergistic cancer therapy augmented by micro/nanoparticles and their biosafety are also included. Some urgent critical issues and potential developments of micro/nanoparticle‐augmented SDT for efficient cancer treatment are addressed. It is highly expected that micro/nanoparticle‐augmented SDT will be quickly developed as a new and efficient therapeutic modality which will find practical applications in cancer treatment. At the same time, fundamental disciplines regarding materials science, chemistry, medicine and nanotechnology will be advanced.     

Titanium-Based Nanoarchitectures for Sonodynamic Therapy-Involved Multimodal Treatments

Sonodynamic therapy (SDT) has considerably revolutionized the healthcare sector as a viable noninvasive therapeutic procedure. It employs a combination of low-intensity ultrasound and chemical entities, known as a sonosensitizer, to produce cytotoxic reactive oxygen species (ROS) for cancer and antimicrobial therapies. With nanotechnology, several unique nanoplatforms are introduced as a sonosensitizers, including, titanium-based nanomaterials, thanks to their high biocompatibility, catalytic efficiency, and customizable physicochemical features. Additionally, developing titanium-based sonosensitizers facilitates the integration of SDT with other treatment modalities (for example, chemotherapy, chemodynamic therapy, photodynamic therapy, photothermal therapy, and immunotherapy), hence increasing overall therapeutic results. This review summarizes the most recent developments in cancer therapy and tissue engineering using titanium nanoplatforms mediated SDT. The synthesis strategies and biosafety aspects of Titanium-based nanoplatforms for SDT are also discussed. Finally, various challenges and prospects for its further development and potential clinical translation are highlighted.     

Two-Dimensional FePS3 Nanosheets as an Integrative Sonosensitizer/Nanocatalyst for Efficient Nanodynamic Tumor Therapy

As the emerging modalities for tumor therapy, sonodynamic therapy (SDT) and chemodynamic therapy (CDT) can generate reactive oxygen species (ROS), typically inducing tumor cell apoptosis. However, the construction of more efficient sonosensitizers integrated with excellent Fenton/Fenton-like catalytic activity to improve the synergistic therapeutic effect of SDT and CDT is still highly challenging. In this study, 2D semiconductor FePS₃ nanosheets (NSs), as one of the metal phosphorus trichalcogenides for both sonosensitizer and Fenton catalyst, are successfully synthesized via an ultrasonic-assisted liquid phase exfoliation method from bulk FePS₃ and further modified with lipoic acid-polyethylene glycol (LA-PEG) to obtain FePS₃-PEG NSs with desirable biocompatibility. The in vitro and in vivo results demonstrate that the engineered FePS₃-PEG NSs induce the combinatorial SDT/CDT effect attributing to the enhanced ROS generation and significant glutathione depletion, which can conduct highly efficient and safe tumor inhibition and prolong the life span of tumor-bearing mice. This work provides the paradigm of semiconductor FePS₃ NSs as the integrative sonosensitizer/Fenton nanocatalyst for dual nanodynamic tumor therapy, paving the new way for exploring other 2D metal phosphorus trichalcogenides in biomedicine.     

Hole Doping and Inhomogeneous Charge Distribution in High T c Cuprates Investigated from First Principles

To understand the link between doping and electronic properties in the high-temperature superconductors, we have performed first-principles calculations for several representatives of high T _c compounds. In the single-layer cuprate HgBa₂CuO₄ the excess oxygen attracts electrons from the CuO₂ plane leading to an increase of the hole concentration in this building block, where the maximum amount of holes is reached when the dopant oxygen shell is closed. The usage of supercells allows to study the inhomogeneous charge distribution as a function of doping, i.e. from the underdoped up to the overdoped regime. Comparison is made with other compounds like Ba-doped La₂CuO₄ and oxygen-deficient YBa₂Cu₃O_7?x . The effects of our findings on superconductivity are discussed.     

A New Sono-Chemo Sensitizer Overcoming Tumor Hypoxia for Augmented Sono/Chemo-Dynamic Therapy and Robust Immune-Activating Response

Novel sonosensitizers with intrinsic characteristics for tumor diagnosis, efficient therapy, and tumor microenvironment regulation are appealing in current sonodynamic therapy. Herein, a manganese (Mn)-layered double hydroxide-based defect-rich nanoplatform is presented as a new type of sono-chemo sensitizer, which allows ultrasound to efficiently trigger reactive oxygen species generation for enhanced sono/chemo-dynamic therapy. Moreover, such a nanoplatform is able to relieve tumor hypoxia and achieve augmented singlet oxygen production via catalyzing endogenous H₂O₂ into O₂. On top of these actions, the released Mn²⁺ ions and immune-modulating agent significantly intensify immune activation and reverse the immunosuppressive tumor microenvironment to the immunocompetent one. Consequently, this nanoplatform exhibits excellent anti-tumor efficacy and effectively suppresses both primary and distant tumor growth, demonstrating a new strategy to functionalize nanoparticles as sono-chemo sensitizers for synergistic combination cancer therapy.     

Inorganic Sonosensitizers for Sonodynamic Therapy in Cancer Treatment

The rapid development of nanomedicine and nanobiotechnology has allowed the emergence of various therapeutic modalities with excellent therapeutic efficiency and biosafety, among which, the sonodynamic therapy (SDT), a combination of low-intensity ultrasound and sonosensitizers, is emerging as a promising noninvasive treatment modality for cancer treatment due to its deeper penetration, good patient compliance, and minimal damage to normal tissue. The sonosensitizers are indispensable components in the SDT process because their structure and physicochemical properties are decisive for therapeutic efficacy. Compared to the conventional and mostly studied organic sonosensitizers, inorganic sonosensitizers (noble metal-based, transition metal-based, carbon-based, and silicon-based sonosensitizers) display excellent stability, controllable morphology, and multifunctionality, which greatly expand their application in SDT. In this review, the possible mechanisms of SDT including the cavitation effect and reactive oxygen species generation are briefly discussed. Then, the recent advances in inorganic sonosensitizers are systematically summarized and their formulations and antitumor effects, particularly highlighting the strategies for optimizing the therapeutic efficiency, are outlined. The challenges and future perspectives for developing state-of-the-art sonosensitizers are also discussed. It is expected that this review will shed some light on future screening of decent inorganic sonosensitizers for SDT.     

Metalloporphyrin Complex‐Based Nanosonosensitizers for Deep‐Tissue Tumor Theranostics by Noninvasive Sonodynamic Therapy

Metal complexes are widely used as anticancer drugs, while the severe side effects of traditional chemotherapy require new therapeutic modalities. Sonodynamic therapy (SDT) provides a significantly noninvasive ultrasound (US) treatment approach by activating sonosensitizers and initiating reactive oxygen species (ROS) to damage malignant tissues. In this work, three metal 4‐methylphenylporphyrin (TTP) complexes (MnTTP, ZnTTP, and TiOTTP) are synthesized and encapsulated with human serum albumin (HSA) to form novel nanosonosensitizers. These nanosonosensitizers generate abundant singlet oxygen (¹O₂) under US irradiation, and importantly show excellent US‐activatable abilities with deep‐tissue depths up to 11 cm. Compared to ZnTTP‐HSA and TiOTTP‐HSA, MnTTP‐HSA exhibits the strongest ROS‐activatable behavior due to the lowest highest occupied molecular orbital?lowest unoccupied molecular orbital gap energy by density functional theory. It is also effective for deep‐tissue photoacoustic/magnetic resonance dual‐modal imaging to trace the accumulation of nanoparticles in tumors. Moreover, MnTTP‐HSA intriguingly achieves high SDT efficiency for simultaneously suppressing the growth of bilateral tumors away from ultrasound source in mice. This work develops a deep‐tissue imaging‐guided SDT strategy through well‐defined metalloporphyrin nanocomplexes and paves a new way for highly efficient noninvasive SDT treatments of malignant tumors.     

Sonodynamic therapy with immune modulatable two-dimensional coordination nanosheets for enhanced anti-tumor immunotherapy

Ultrasound with deep penetration depth and high security could be adopted in sonodynamic therapy(SDT)by activating sonosensitizers to generate cytotoxic reactive oxygen species(ROS).Herein,two-dimensional(2D)coordination nanosheets composed of Zn²⁺and Tetrakis(4-carboxyphenyl)porphyrin(TCPP)are fabricated.While exhibiting greatly enhanced ultrasoundtriggered ROS generation useful for noninvasive SDT,such Zn-TCPP 2D nanosheets show high loading capacity of oligodeoxynudeotides such as cytosine—phosphorothioate-guanine(CpG),which is a potent toll like receptor 9(TLR9)agonist useful in activating immune responses.Highly effective SD T of primary tumors could release tumor-associated antigens,which working together with Zn-TCPP/CpG adjuvant nanosheets could function like whole-tumor-cell vaccines and trigger tumor-specific immune responses.Interestingly,ultrasound itself could strengthen anti-tumor immune responses by improving the tumor-infiltration of T cells and limiting regulatory T cells in the tumor microenvironment.Thus,SDT using Zn-TCPP/CpG nanosheets after destruction of primary tumors could induce potent antitumor immune responses to inhibit distant abscopal tumors without direct SD T treatment.Moreover,SDT with Zn-TCPP/CpG could trigger strong immunological memory effects to inhibit cancer recurrence after elimination of primary tumors.Therefore,the 2D coordination nanosheet may be a promising platform to deliver potent SDT-triggered immunotherapy for highly effective cancer treatment.     

Hole Doping and Inhomogeneous Charge Distribution in High Tc Cuprates Investigated from First Principles

To understand the link between doping and electronic properties in the high-temperature superconductors, we have performed first-principles calculations for several representatives of high T _c compounds. In the single-layer cuprate HgBa₂CuO₄ the excess oxygen attracts electrons from the CuO₂ plane leading to an increase of the hole concentration in this building block, where the maximum amount of holes is reached when the dopant oxygen shell is closed. The usage of supercells allows to study the inhomogeneous charge distribution as a function of doping, i.e. from the underdoped up to the overdoped regime. Comparison is made with other compounds like Ba-doped La₂CuO₄ and oxygen-deficient YBa₂Cu₃O_7–x . The effects of our findings on superconductivity are discussed.     

Mesenchymal Stem Cells Functionalized Sonodynamic Treatment for Improving Therapeutic Efficacy and Compliance of Orthotopic Oral Cancer

Despite multiple treatment options being available, many critical challenges are still ongoing in the treatment of oral squamous cell carcinoma (OSCC). Particularly, the major hurdle is to avoid facial disfigurement and oral function disability during treatment. Herein, nanoengineered mesenchymal stem cells (MSCs) are developed as a supersonosensitizer, named M/LPV/O₂, for improving nondestructive sonodynamic therapy (SDT) against OSCC along with good therapeutic compliance. M/LPV/O₂ is composed of an MSCs membrane functionalized liposomal formulation of oxygen-loading perfluorocarbon and sonosensitizer verteporfin (M/LPV/O₂), which can not only increase circulation and targeting efficacy but also supply oxygen to overcome tumor-hypoxia-associated resistance in SDT, resulting in enhanced therapeutic outcomes in vitro and in vivo. It is identified that M/LPV/O₂ effectively stimulates the generation of reactive oxygen species even in hypoxic conditions, and consequently tremendously induces cancer cell death. In addition, M/LPV/O₂ displays good tumor accumulation and penetration under ultrasound stimulation, and efficiently induces tumor inhibition and even abrogation, leading to prolonged survival of tumor-bearing mice. Importantly, M/LPV/O₂-based SDT exhibits minimal systemic adverse effects and successfully maintains oral functions with no facial tissue damage. Therefore, these studies provide a promising therapeutic strategy for OSCC, which has a potential to enhance life quality and compliance after treatment.     

Effects of samarium dopant on photocatalytic activity of TiO<Subscript>2</Subscript> nanocrystallite for methylene blue degradation

Sm³⁺-doped TiO₂ nanocrystalline was synthesized by a sol–gel auto-combustion method and characterized by X-ray diffraction, Brunauer-Emmett-Teller method (BET), UV–vis diffuse reflectance spectroscopy (DRS), and also photoluminescence (PL) emission spectroscopy. The photocatalytic activity of Sm³⁺–TiO₂ catalyst was evaluated by measuring degradation rates of methylene blue (MB) under either UV or visible light. The results showed that doping with the samarium ions significantly enhanced the photocatalytic activity for MB degradation under UV or visible light irradiation. This was ascribed to the fact that a small amount of samarium dopant simultaneously increased MB adsorption capacity and separation efficiency of electron-hole pairs. The results of DRS showed that Sm³⁺-doped TiO₂ had significant absorption between 400 nm and 500 nm, which increased with the increase of samarium ion content. The adsorption experimental demonstrated that Sm³⁺–TiO₂ had a higher MB adsorption capacity than undoped TiO₂ and adsorption capacity of MB increased with the increase of samarium ion content. It is found that the stronger the PL intensity, the higher the photocatalytic activity. This could be explained by the points that PL spectra mainly resulted from surface oxygen vacancies and defects during the process of PL, while surface oxygen vacancies and defects could be favorable in capturing the photoinduced electrons during the process of photocatalytic reactions, so that the recombination of photoinduced electrons and holes could be effectively inhibited.     

Modifying the oxygen adsorption properties of YBaCo<Subscript>4</Subscript>O<Subscript>7</Subscript> by Ca,Al, and Fe doping

The doping effect of Ca, Al, and Fe on the oxygen adsorption properties of YBaCo₄O₇ was investigated by thermogravimetry (TG) method. It was found that the original YBaCo₄O₇ oxygen adsorption properties can be modified greatly by Ca, Al, and Fe doping. Ca doping in Y sites eliminates the oxygen adsorption at low temperature (~300 °C) but the oxygen adsorption properties at high temperature is almost unchanged. Minor Al doping in Co sites eliminates the oxygen adsorption hump at high temperature, but the hump at low temperature is preserved. Fe appearance in YBaCo₃Al_1−x Fe _x O₇ seems to weaken the effect of Al doping, so the oxygen hump at high temperature emerges again. The doping effect was discussed based on elements valence, binding energy between cations and oxygen ions, and distortion of crystal structure.     

Recent Advances in Nanomaterial-Assisted Combinational Sonodynamic Cancer Therapy

Ultrasound (US)-triggered sonodynamic therapy (SDT), as a promising noninvasive therapeutic modality, has received ever-increasing attention in recent years. Its specialized chemical agents, named sonosensitizers, are activated by low-intensity US to produce lethal reactive oxygen species (ROS) for oncotherapy. Compared with phototherapeutic strategies, SDT provides many noteworthy opportunities and benefits, such as deeper penetration depth, absence of phototoxicity, and fewer side effects. Nevertheless, previous studies have also demonstrated its intrinsic limitations. Thanks to the facile engineering nature of nanotechnology, numerous novel nanoplatforms are being applied in this emerging field to tackle these intrinsic barriers and achieve continuous innovations. In particular, the combination of SDT with other treatment strategies has demonstrated a superior efficacy in improving anticancer activity relative to that of monotherapies alone. Therefore, it is necessary to summarize the nanomaterial-assisted combinational sonodynamic cancer therapy applications. Herein, the design principles in achieving synergistic therapeutic effects based on nanomaterial engineering methods are highlighted. The ultimate goals are to stimulate the design of better-quality combined sonodynamic treatment schemes and provide innovative ideas for the perspectives of SDT in promoting its future transformation to clinical application.     

Piezocatalytic Tumor Therapy by Ultrasound-Triggered and BaTiO3-Mediated Piezoelectricity

Ultrasound theranostics features non-invasiveness, minor energy attenuation, and high tissue-penetrating capability, and is playing ever-important roles in the diagnosis and therapy of diseases in clinics. Herein, ultrasound is employed as a microscopic pressure resource to generate reactive oxygen species (ROS) for piezocatalytic tumor therapy under catalytic mediation by piezoelectric tetragonal BaTiO₃ (T-BTO). Under the ultrasonic vibration, the electrons and holes are unpaired and they are separated by the piezoelectricity, resulting in the establishment of a strong built-in electric field, which subsequently catalyzes the generation of ROS such as toxic hydroxyl (^•OH) and superoxide radicals (^•O₂⁻) in situ for tumor eradication. This modality shows intriguing advantages over typical sonoluminescence-activated sonodynamic therapy, such as more stable sensitizers and dynamical control of redox reaction outcomes. Furthermore, according to the finite element modeling simulation, the built-in electric field is capable of modulating the band alignment to make the toxic ROS generation energetically favorable. Both detailed in vitro cellular level evaluation and in vivo tumor xenograft assessment have demonstrated that an injectable T-BTO-nanoparticles-embedded thermosensitive hydrogel will substantially induce ultrasound irradiation-triggered cytotoxicity and piezocatalytic tumor eradication, accompanied by high therapeutic biosafety in vivo.     

2D Piezoelectric BiVO4 Artificial Nanozyme with Adjustable Vanadium Vacancy for Ultrasound Enhanced Piezoelectric/Sonodynamic Therapy

Increasing the yield of reactive oxygen species (ROS) to enhance oxidative stress in cells is an eternal goal in cancer therapy. In this study, BiVO₄ artificial nanozyme is developed with adjustable vanadium vacancy for ultrasound (US) enhanced piezoelectric/sonodynamic therapy. Under US excitation, the vanadium vacancy-rich BiVO₄ nanosheets (abbreviated V_v-r BiVO₄ NSs) facilitate the generation of a large number of electrons to improve the ROS yield. Meanwhile, the mechanical strain imposed by US irradiation makes the V_v-r BiVO₄ NSs display a typical piezoelectric response, which tilts the conduction band to be more negative and the valance band more positive than the redox potentials of O₂/O₂^•− and H₂O/·OH, boosting the efficiency of ROS generation. Both density functional theory calculations and experiments confirm that the introduction of cationic vacancy can improve the sonodynamic effect. As expected, V_v-r BiVO₄ NSs have better peroxidase enzyme catalytic and glutathione depletion activities, resulting in increased intracellular oxidative stress. This triple amplification strategy of oxidative stress induced by US substantially inhibits the growth of cancer cells. The work may open an avenue to achieve a synergetic therapy by introducing cationic vacancy, broadening the biomedical use of piezoelectric materials.