To date, numerous medical technologies have been developed, yet few can accommodate the diverse range of clinical applications. As a result, there is an urgent need to explore innovative and effective disease treatment strategies [1]. The employment of nanomaterials and nanotechnologies has garnered significant attention in recent decades, as various nanomedicines have demonstrated substantial success in enhancing therapeutic efficacy while reducing side effects ^[2][3][4][2,3,4]. Among these, piezoelectric materials have emerged as promising candidates for medical applications due to their unique piezoelectric properties, which enable stress-induced electric activation and can be triggered by external mechanical sources.

First discovered by P. Curie and J. Curie in 1880, piezoelectricity refers to the ability of certain materials to convert vibrational energy into an electric field in response to stress [5], a phenomenon later defined as the piezoelectric effect. Conversely, when an electric field is applied to a piezoelectric material in the polarization direction, the material deforms, releasing mechanical energy, and the inverse piezoelectric effect occurs [6]. Subsequent research over the following two centuries has elucidated the mechanisms of piezo-catalysis, employing screening charge effects and energy band theory [7].

Materials possessing the piezoelectric effect are capable of converting mechanical stress into electrical energy, thereby stimulating cells or interfering with their surrounding electric field. Consequently, piezoelectric materials can influence electron transport in vivo, acting on various physiological tissues such as stem cells, muscles, neurons, and embryogenesis, and interfering with their physiological activities. Presently, invasive electrodes are employed to apply −10 to −90 mV of electricity to alter the membranes of living cells. Following the modification of the endogenous electric field, ions such as Ca²⁺, Na⁺, and K⁺ move directionally, controlling cell excitation or inhibition (particularly in neurons) directly or by adjusting protein/ion channel conformation and expression, ultimately regulating signal pathways, and manipulating gene expression or neurotrophin levels [8].

Another mechanism involves the initiation of electrochemical reactions by electricity, impacting cells and biological processes [9]. The piezoelectric effect can induce effective interfacial charge transfer, thereby promoting the exceptional redox catalytic activities of piezoelectric materials. Numerous electrons and holes can be released from piezoelectric materials to catalyze redox reactions of water and other substrates when exposed to mechanical energy ^[10][11][10,11]. This process subsequently generates reactive oxygen species (ROS) that directly oxidize nearby biomolecules, damaging cancer cells or sterilizing tissues without penetration limitations ^[12][13][14][12,13,14].

Ultrasound is a well-established noninvasive and nonionizing diagnostic technology, operating within a frequency range of 2.5 to 15 MHz under diagnostic conditions. The mechanical and thermal effects of ultrasound at around 1 MHz are frequently utilized in various treatments. Additionally, ultrasound has the ability to increase the permeability of the gastric mucosa and blood–brain barrier ^[15][16][15,16]. Certain advantages of ultrasound, such as noninvasiveness and mechanical effects, enable its use in the controlled delivery and release of drugs.

In contrast to traditional therapies that rely on electrical stimuli and require invasive percutaneous electrodes or transcutaneous devices, wireless treatment methods employing piezoelectric nanoparticles represent a new paradigm, as they are activated by external ultrasound (US). The combination of piezoelectric nanoparticles and US allows for wireless induction of local electrical stimulation within the body [17], circumventing issues of infection and biocompatibility associated with invasive electrodes. Consequently, electrical stimuli can be directly transmitted to target tissues with high spatial precision via an in vitro wireless mechanical trigger, such as US equipment, harnessing the piezoelectric effects of nanoparticles [18]. As a result, piezoelectric materials hold promise for improving electrical stimulation treatments activated by the mechanical effects of ultrasound.

Piezoelectric materials exhibit two distinct responses to external stimuli: the direct piezoelectric effect, which involves the generation of electrical energy under mechanical pressure, and the reverse piezoelectric effect, characterized by mechanical deformation caused by electrical stimulation. A fundamental equation can be employed to describe the direct piezoelectric effect as follows:

In this equation, D represents the electric displacement, d and T denote the piezoelectric coefficient and the applied stress, respectively, while ε and E correspond to the material’s dielectric constant and the electric field, respectively [19]. The piezoelectric coefficients of common piezoelectric materials are provided in Table 1 [20].

Piezoelectric materials can be fundamentally classified into three categories: inorganic, organic, and composite materials. Inorganic piezoelectric materials primarily consist of piezoelectric crystals and ceramics. Piezoelectric crystals were the earliest studied materials, dating back to the 1940s. The underlying mechanism involves external force altering the net dipole from zero to a nonzero value, which leads to a distinct electrically neutral arrangement, culminating in a positive center and a negative center and ultimately resulting in the material’s electrical polarization ^[21][22][21,22]. Piezoelectric crystals can be single crystals, such as SiO₂, Rochelle salt, potassium dihydrogen phosphate (KDP), ammonium dihydrogen phosphate (ADP), or polycrystalline, including BaTiO₃ (BTO), lead zirconate titanate (PZT), and PbTiO₃ (non-ferroelectric piezoelectric) [23]. Piezoelectric ceramics are compounds formed after heating, with each tiny part polarizing in the same direction under the same external force, causing the material to polarize as a whole. However, the toxicity of piezoelectric ceramics renders them unsuitable for direct use within the body. Organic piezoelectric materials also referred to as piezoelectric polymers, can be divided into synthetic polymers and natural polymers [23]. Synthetic piezoelectric polymers, such as polyvinylidene fluoride (PVDF) films, exhibit flexibility, low density, low impedance, and a high piezoelectric voltage constant (g). Furthermore, their acoustic impedance is closely aligned with air, water, and biological tissue, making them particularly suitable for the fabrication of liquid, biological, and gas transducers. Additionally, certain natural materials possess favorable piezoelectric properties, including peptides, collagen, and amino acids. As a result, these materials can be employed to transfer electricity through tissues at various stages of life, not only during embryogenesis but also in adult organisms, to regulate adaptation, development, and healing processes [18]. Composite piezoelectric materials consist of two or more types of materials combined. A typical structure involves piezoelectric materials in sheet, rod, or powder form embedded within an organic polymer-based material. Such composites possess the advantages of both piezoelectric ceramics and polymer materials and have been extensively utilized in medical research. One example is the composite of piezoelectric ceramics and polymers (PVDF or others).

In general, piezoelectric ceramics exhibit higher piezoelectric coefficients, indicating their energy conversion efficiency. Conversely, piezoelectric polymers possess lower dielectric constants, representing their charge storage capability. Piezoelectric composites amalgamate the advantages of various materials to achieve specific objectives ^{[19][20][21][22][23][24]}[19,20,21,22,23,24].

Piezoelectric nanomaterials, which can be standalone materials or composites, exhibit unique physical properties such as electric field strength and dielectric constant, biological properties such as targeting and biocompatibility, chemical properties of composition and stability, etc. These properties can be tailored and enhanced through various approaches, including covalent and non-covalent modifications, as well as through the incorporation of other functional nanomaterials [25].

When piezoelectric materials are converted into nanoparticles, their piezoelectric properties may either increase or decrease. For instance, incorporating Zn_0.25Co_0.75Fe₂O₄, ZCFO, and BTO particles into PVDF-TrFE polymers enhances physical properties, such as increased electric coefficients, reduced response lags, and improved stiffness during bone tissue repair [26].

Crystalline structure and nanoparticle size are vital characteristics of nanomaterials that need monitoring. Techniques such as X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), piezoelectric response force microscopy (PFM), and tunneling atomic force microscopy (TUNA) are utilized to observe piezoelectric properties, while density functional theory (DFT) can be employed for predicting and understanding the material behavior [27].

Regarding biocompatibility, although certain piezoelectric materials such as lead zirconate titanate (PZT) contain toxic Pb, making their use as implantable materials contentious [28], improved biocompatibility can be achieved by coating the PZT surface with titanium [29]. Inorganic nanoparticles must acquire biocompatibility through coating before in vivo use [30], whereas organic polymers inherently possess biocompatibility. The evaluation of biosafety regarding nanoparticle shape, size, and interaction with the bio-environment is always necessary.

As mentioned in the introduction, piezoelectric nanomaterials produce electricity to stimulate cells or tissues, influencing cell growth, development, proliferation, and other behaviors by affecting ions and electro-sensitive proteins. Additionally, piezoelectricity can generate reactive oxygen species (ROS) promoted by piezoelectrically polarized charges. The generated ROS induces apoptosis through oxidative stress and mediated DNA damage, making piezoelectric nanomaterials widely utilized in antitumor and pathogen clearance [31].

Electrical stimulation, a noninvasive and nonpharmacological physical stimulus, has extensive biomedical effects. It has been employed for muscle rehabilitation, treatment of movement/consciousness disorders, drug delivery, and wound healing. At the molecular level, electrical stimulation (ES) facilitates biomolecule transport through biofilms via electrophoresis and electro-penetration. At the subcellular level, electrical stimulation interacts with the cytoskeleton, membrane proteins, ion channels, and various intracellular organelles, altering cellular activities and functions such as contraction, migration, orientation, and proliferation [32].

In addition to the direct application of electrical stimulation, external mechanical forces can separate the charges of piezoelectric nanomaterials and generate ROS that impact biological systems [33]. Under mechanical vibrations, piezoelectric materials establish dynamic built-in electric fields, continuously separating electron and hole pairs for piezoelectric catalytic redox reactions, generating reactive oxygen species (ROS) such as toxic hydroxyl groups (•OH) and superoxide radicals (•O²⁻). Due to the nanosize effect, piezoelectric nanomaterials generally exhibit superior piezoelectric effects compared to macroscopic bulk structures [18].