Sonodynamic therapy (SDT) shows substantial potentials in cancer treatment thanks to the deep tissue penetration of ultrasound. However, its clinical translation suffers from the potential damages to healthy tissues and the resistance of tumors, particularly from cancer stem-like cells (CSCs), to the ultrasound. To address these challenges, we designed a novel glutathione (GSH)-activated nanomedicine to simultaneously enhance the safety and efficacy of SDT by in situ regulating the generation of reactive oxygen species (ROS) and copper metabolism. This nanomedicine, Es@CuTCPP, was created by loading elesclomol (Es) onto CuTCPP nanosheets. By accumulating this nanomedicine in tumors, the Cu(II)-TCPP is reduced to the highly sonosensitive Cu(I)-TCPP by the intra-tumoral-overexpressed GSH, leading to the production of abundant ROS upon ultrasound exposure, which effectively kills large amounts of tumor cells. Concurrently, the released copper ions react with co-released Es to form a CuEs complex, which induces cuproptosis of CSCs surviving the ROS attack by disrupting cellular copper metabolism, evidently amplifying the effectiveness of SDT. This work presents the first paradigm of a GSH-activated and cuproptosis-enhanced SDT approach, offering a promising novel strategy for cancer therapy.

Safe and efficient drug delivery is as important as drug development. Biological barriers, such as cell membranes, present significant challenges in drug delivery, especially for newly developed protein-, nucleic acid-, and cell-based drugs. Ultrasound-mediated drug delivery systems offer a promising strategy to overcome these challenges. Ultrasound, a mechanical wave with energy, produces thermal effects, cavitation, acoustic radiation, and other biophysical effects. Used alone or in combination with microbubbles or sonosensitizers, it breaks biological barriers, enhances targeted drug delivery, reduces adverse reactions, controls drug release, switches on/off drug functions, and ultimately improves therapeutic efficiency. Various ultrasound-mediated drug delivery methods, including transdermal drug delivery, nebulization, targeted microbubble destruction, and sonodynamic therapy, are being actively explored for the treatment of various diseases. This review article introduces the principles, advantages, and applications of ultrasound-mediated drug delivery methods for improved therapeutic outcomes and discusses future prospects in this field.

Sonodynamic therapy (SDT) has attracted widespread attention in treatment of implant-associated infections, one of the key factors leading to implant failure. Nevertheless, constructing efficient ultrasound-triggered coatings on implant surfaces remains a challenge. Herein, an acoustic metastructure Cu-doped defective titanium oxide coating (Cu-TiO x ) with lattice strain was constructed in situ on titanium implant to realize effective sonocatalysis. The redistribution of Cu atoms broke the pristine lattice of TiO2 during the thermal reduction treatment to regulate its energy structure, which favored separation of electron-hole pairs generated by ultrasound radiation to enhance the sonocatalytic generation of reactive oxygen species. In addition, the acoustic metastructure enhanced the absorption of ultrasound by Cu-TiO x metastructure coating, which further promoted its sonocatalytic effect. Thus, Cu-TiO x metastructure coating could efficiently eliminate Staphylococcus aureus and Escherichia coli infections under ultrasonic irradiation in 10 min. Besides, the osteogenic property of implant was significantly improved after infection clearance in vivo. This work provides a fresh perspective on the design of SDT biosurfaces based on metastructure and strain-defect engineering.

The development of novel microspheres for the combination of sonodynamic therapy (SDT) with transarterial embolization (TAE) therapy to amplify their efficacy has received increasing attention. Herein, a novel strategy for encapsulating sonosensitizers (e.g., oxygen-deficient manganese tungstate (MnWOX) nanodots) with gelatin microspheres was proposed. The obtained MnWOX-encapsulated microspheres (abbr. Mn-GMSs) facilitated efficient sonodynamic-embolization-metalloimmune therapy via the immune effects of metal ions on orthotopic liver cancer tumor after transarterial embolization (TAE). Due to the strong cavitation effect caused by the porous structure, Mn-GMSs exhibited a greater reactive oxygen species (ROS) generation rate than the free MnWOX nanodots under US irradiation. Efficient SDT revealed robust cell-killing effects and triggered strong immunogenic cell death (ICD). Moreover, the Mn ions released from the bioactive Mn-GMSs further stimulated the dendritic cells (DCs) maturation and triggered the activation of the cGAS/STING pathway to enhance the immunological effect. Thus, Mn-GMSs achieved significant SDT therapeutic outcomes in H22 tumors in mice, and the combination of the Mn-GMSs triggered SDT with programmed cell death ligand 1 (PD-L1) antibodies could further enhance therapeutic outcomes. The Mn-GMSs exhibited high ROS generation efficacy under US irradiation, significant immune activation, good efficacy in combination with immune checkpoint inhibitor, and great potential for artery embolization-assisted drug delivery, thus enabling effective destruction of liver tumors in rats and rabbits. Therefore, this work provides a strategy for applying SDT in deep tumors and highlights a promising sonodynamic-embolization therapy for combating liver cancers.

Central nervous system (CNS) cancers, particularly glioblastoma (GBM), are associated with high mortality and disability rates. Despite aggressive surgical resection, radiotherapy, and chemotherapy, patient survival remains poor. The blood-brain barrier (BBB) significantly impedes therapeutic efficacy, making BBB penetration a critical focus of research. Focused ultrasound (FUS) combined with microbubbles (MBs) can transiently open the BBB through mechanisms such as cavitation, modulation of tight junction protein expression, and enhanced vesicular transport in endothelial cells. This review highlights precision delivery and personalized treatment strategies under ultrasound visualization, including precise control of ultrasound parameters and modulation of the immune microenvironment. We discuss the applications of ultrasound-responsive nanoparticles in brain tumor therapy, including enhanced radiotherapy, gene delivery, immunotherapy, and sonodynamic therapy (SDT), with a particular emphasis on piezoelectric catalytic immunotherapy. Finally, we provide insights into the clinical translation potential of ultrasound-responsive nanoparticles for personalized and precision treatment of brain tumors.

The development of antibiotic resistance and inadequate immune response in chronic inflammation pose significant challenges in treating chronic osteomyelitis. As accepted non-antibiotic antimicrobial therapies, sonodynamic therapy (SDT) and photothermal therapy (PTT) are recognized for their effectiveness in eliminating bacteria and promoting tissue repair, rendering them promising therapeutic strategies for treating bacterial infections and preventing the emergence of drug-resistant bacteria. However, the antimicrobial action and efficacy in promoting tissue repair depend on the activation status of the host immune system. In this study, by encapsulating horseradish peroxidase (HRP)-loaded gold/polydopamine (PDA) nanoparticles within DOTAP/DOPE cationic liposomes (DLPs), a novel multifunctional nanocatalyst, Au/PDA/HRP@DLP (APH@DLP), was developed to achieve antimicrobial effects and immunological reprogramming of chronic osteomyelitis through synergistic SDT and PTT. The impact on immune activation was investigated by assessing the anti-infective and healing effects in osteomyelitis rat models. The release of bacterial-associated antigens during treatment serves as an in situ vaccine, activating antigen-presenting cells and further stimulating adaptive immunity, while also inducing immune memory that significantly reduces the risk of recurrence. Additionally, macrophage phenotypic transformation during SDT and PTT facilitates tissue repair. This study highlights the role of immune activation in SDT/PTT-based antimicrobial therapy and suggests new strategies for treating chronic osteomyelitis.

Abnormalities in glucose metabolism have been shown to characterize malignant tumors. Glucose depletion by glucose oxidase (GOD) has shown great potential in tumor therapy by causing tumor starvation. Since 2017, nanomedicines have been designed and utilized to deliver GOD for more precise and effective glucose modulation, which can overcome intrinsic limitations of different cancer therapeutic modalities by remodeling the tumor microenvironment to enhance antitumor therapy. To date, the topic of GOD-delivering nanomedicines for enhancing tumor therapy has not been comprehensively summarized. Herein, this review aims to provide an overview and discuss in detail recent advances in GOD delivery and directly involved starvation therapy strategies, GOD-sensitized various tumor therapy strategies, and GOD-mediated multimodal antitumor strategies. Finally, the challenges and outlooks for the future progress of the emerging tumor therapeutic nanomedicines are discussed. This review provides intuitive and specific insights to a broad audience in the fields of nanomedicines, biomaterials, and cancer therapy.

Breast cancer (BC) is a global threat to female health. Sonodynamic therapy (SDT) has been shown to induce apoptosis in tumor cells and trigger immunogenic cell death, leading to the activation of antitumor immunity. However, the immunogenicity of this process may be compromised by oxidative stress and proteolysis. Necroptosis caused by ultrasound-targeted nanobubble destruction (UTND) could boost immunity. Therefore, we tested if necroptosis-inducible nanobubbles (NB) could enhance sonodynamic immunotherapy for BC. We also assessed whether O2-filled NB could address tumor hypoxia and enhance SDT efficacy.

A novel multifunctional nano-system, comprising NB for UTND encapsulating chlorin e6 (Ce6) for SDT and O2 for hypoxia alleviation was established. Ce6-O2NB cytocompatibility and intracellular uptake was studied in vitro, as well as whether Ce6-O2NB could generated reactive oxygen species when exposed to ultrasound irradiation in order to induce apoptosis in tumor cells. In vivo pharmacokinetics, therapeutic efficacy, and immune activation after Ce6-O2NB treatment were studied in 4T1 tumor-bearing mice.

Ce6-O2NB had a well-designed core-shell structure and desirable biocompatibility and safe therapeutic effects. Ce6-O2NB was able to load both ce6 and oxygen to increase ce6 and oxygen accumulation in tumors. After triggering by ultrasound, Ce6-O2NB generated reactive oxygen species (ROS) and acted as sonosensitizers for SDT, promoting tumor cell death through apoptotic and/or necrotic mechanisms. Furthermore, antitumor immunity was activated by stimulation of spleen lymphocyte proliferation and cytotoxicity, and increasing cytotoxic T lymphocyte numbers. Combination of oxygen with SDT ultimately strengthened its antitumor effects. In addition, Ce6-O2NB alleviated tumor hypoxia, induced increased ROS generation, and improved immune responses and therapeutic efficacy of SDT. Ce6-O2NB also facilitated fluorescence and contrast-enhanced ultrasound imaging.

Ce6-O2NB can mitigate tumor hypoxia, enhance SDT, and activate antitumor immunity by inducing simultaneous immunogenic apoptosis and necroptosis, ultimately activating antitumor immunity and inhibiting breast tumor growth in mice.

Sonodynamic therapy (SDT) is a novel non-invasive treatment method that combines low-intensity ultrasound and sonosensitizers. Compared with photodynamic therapy, SDT has the advantages of deeper tissue penetration, higher accuracy and fewer adverse reactions. Sonosensitizers are essential for the efficacy of SDT. Sonosensitizers have the advantages of clear structure, easy monitoring, evaluation of drug metabolism and clinical transformation, etc. Notably, biochemical techniques can be used in the field of sonosensitizers and SDT to overcome inherent barriers and achieve sustainable innovation. This article first summarizes the molecular mechanism of SDT, focusing on organic sonosensitizers, inorganic nano-sonosensitizers and multi-functional drug delivery systems with targeting, penetration and imaging functions after a series of modifications. This review provides ideas and references for the design of sonosensitizers and SDT and promotes their future transformation into clinical applications.

In practical clinical scenarios, improved diagnostic methods have been developed for the precise visualization of molecular targets using molecular imaging in brain diseases. Recently, the introduction of innovative molecular imaging modalities across both macroscopic and mesoscopic dimensions, with remarkable specificity and spatial resolution, has expanded the scope of applications beyond diagnostic testing, with the potential to guide therapeutic interventions, offering real-time feedback in the context of brain therapy. The molecular imaging-guided integration of diagnosis and treatment holds the potential to revolutionize disease management by enabling the real-time monitoring of treatment responses and therapy adjustments. Given the vibrant and ever-evolving nature of this field, this review provides an integrated picture on molecular image-guided diagnosis and treatment integration for brain diseases involving the basic concepts, significant breakthroughs, and recent trends. In addition, based on the current achievements, some critical challenges are also discussed.

Sonodynamic therapy (SDT) has emerged as a promising noninvasive approach for tumor therapy. However, the effectiveness of traditional inorganic semiconductor sonosensitizers is hindered by rapid electron (e-) and hole (h+) recombination under ultrasonic (US) stimulation, as well as the hypoxic and reductive conditions of tumor microenvironment (TME), which limit the generation of reactive oxygen species (ROS). Herein, a ruthenium (Ru) single-atom nanozyme-driven superimposition-enhanced titanium dioxide-based sonosensitizer (Ru/TiO2-x SAE) is presented that features sufficient oxygen vacancies and high e-/h+ separation efficiency. Through synchrotron radiation-based X-ray absorption spectroscopy and extended X-ray absorption fine structure analysis it is confirmed that oxygen vacancies in TiO2-x nanoparticles promote the immobilization of single-atomic Ru, forming Ru-O₄ active sites. Density functional theory calculations demonstrate that oxygen vacancies alter the electronic structure of nanosensitizer, enhanced e-/h+ separation, increasing oxygen adsorption, and accelerating reaction kinetics under US stimulation, ultimately improving ROS production. Moreover, Ru/TiO2-x SAE boosts sonodynamic efficacy by mitigating the hypoxic and reductive TME. This is attributed to its catalase- and glutathione peroxidase 4-like activities, which facilitate the generation of ROS and trigger lipid peroxidation-mediated ferroptosis. These findings highlight the innovative role of single-atom Ru in optimizing sonosensitizers for SDT-induced ferroptosis, demonstrating its potential for advancing cancer therapy.

Harnessing immunostimulation to reinvigorate antitumor effector immune cells represents a promising strategy for tumor eradication. However, achieving durable clinical outcomes necessitates multidimensional activation to sustain robust immune responses. Here, we present an ultrasound-empowered living biohybrid that strategically mobilizes T-cell-mediated immunity for potent tumor sono-immunotherapy. Through synthetic biology, we engineer bacteria to express a fusion protein encoding the costimulatory OX40 ligand (OX40L), and further functionalize them with a high-performance polymer sonosensitizer tethered via a reactive oxygen species-cleavable linker. Upon ultrasound irradiation, the sono-activated nanocargoes detach from the bacterial surface, facilitating cellular entry and exposing immune-stimulating OX40L. The potent sonodynamic effects, coupled with the native immunogenicity of bacteria, promotes tumor-associated antigen release, fosters a proinflammatory microenvironment, and drives dendritic cell maturation, thereby priming cytotoxic T-cell activation. The OX40L expressed by the engineered bacteria amplifies and sustains T-cell activity, orchestrating a robust and durable antitumor response. This cascade-amplified immune activation effectively suppresses tumor growth, induces long-lasting immune memory, and provides protection against tumor metastasis and recurrence, significantly enhancing survival outcomes. By integrating ultrasound-energized nanoadjuvants with costimulatory immune boosters, this hybrid living biotherapeutic platform offers a versatile and powerful strategy for multidimensional immune activation, advancing the frontier of cancer sono-immunotherapy.

In situ vaccination (ISV) has emerged as a promising strategy in cancer immunotherapy, offering a targeted approach that uses the tumor microenvironment (TME) to stimulate an immune response directly at the tumor site. This method minimizes systemic exposure while maintaining therapeutic efficacy and enhancing safety. Recent advances in nanotechnology have enabled new approaches to ISV by utilizing nanomaterials with unique properties, including enhanced permeability, retention, and controlled drug release. ISV employing nanomaterials can induce immunogenic cell death and reverse the immunosuppressive and hypoxic TME, thereby converting a "cold" tumor into a "hot" tumor and facilitating a more robust immune response. This review examines the mechanisms through which nanomaterials-based ISV enhances anti-tumor immunity, summarizes clinical applications of these strategies, and evaluates its capacity to serve as a neoadjuvant therapy for eliminating micrometastases in early-stage cancer patients. Challenges associated with the clinical translation of nanomaterials-based ISV, including nanomaterial metabolism, optimization of treatment protocols, and integration with other therapies such as radiotherapy, chemotherapy, and photothermal therapy, are also discussed. Advances in nanotechnology and immunotherapy continue to expand the possible applications of ISV, potentially leading to improved outcomes across a broad range of cancer types.

Exosomes are naturally occurring nanocarriers derived from various cells. In recent years, they have attained significant attention for their potential in precise drug delivery and therapeutic applications. Exosomes exhibit several advantages, remarkably improved stability, bioavailability, and delivery efficiency, which are further augmented by integration with nanomaterials. Functionalizing the aptamer and nanomaterial on the exosomal surface significantly improves the binding affinity and specificity. Here in this review, we examine the synergistic therapeutic effect of exosome-nanomaterial-aptamer conjugate with particular attention to their uses in cancer therapy, bone fracture regeneration, wound healing, etc. Recent advances in the field demonstrated that the amalgamation of different nanomaterials, aptamers, and exosomes has proven to be a transformative approach in the field of therapeutics. Here in the nanocomposite, the aptamer is exclusively used as a recognition molecule to provide specificity to the target cells. Exosomes serve as biocompatible nanocarriers, and different nanomaterials (AuNPs, AuNRs, SiNPs, Graphene, etc.) complement the therapeutic efficiency by PTT/PDT/ROS generation/SO generation, etc. Briefly, the above-mentioned nanocomposite serves as the perfect therapeutic agent by utilizing the exosome's biocompatibility, aptamer's high affinity and nanomaterial's multifunctionality. Furthermore, the challenges and limitations of this nanocomposite have been discussed, along with its prospects in clinical practices.

Low-intensity pulsed ultrasound (LIPUS) is an effective ancillary treatment modality for various malignancies. However, the mechanisms underlying the role of LIPUS in cancer treatment have not been fully elucidated. We investigated the effects and underlying mechanism of LIPUS on the proliferation, apoptosis, migration, and invasion of hepatocellular carcinoma (HCC) cells.

The HCC cell lines SMMC7721 and HCCLM3 were exposed to 1 MHz LIPUS at intensities of 0.5, 1.0, 1.5 W/cm2 for 60 s. Cell morphology, viability, apoptosis, colony formation, migration, and invasion were assessed. Intracellular reactive oxygen species (ROS) levels and mitochondrial membrane potential were evaluated using a ROS assay kit and a JC-1 staining kit. Western blotting was performed to quantify changes in matrix metallopeptidases and epithelial-mesenchymal transition-related proteins. Orthotopic Hep3B-Luc tumor-bearing mice were treated with LIPUS at 1.5 W/cm2 or 0 W/cm2 and growth trend was measured.

The results showed that different intensities of ultrasound affected cellular activity, inhibited cell proliferation and cloning, facilitated intracellular cytoskeletal protein reorganization, and induced cell apoptosis, particularly at the intensity of 1.5 W/cm2, through the ROS/mitochondria pathway. LIPUS enhanced SMCC7721 and HCCLM3 cell migration and invasion in a dose-dependent manner by regulating matrix metallopeptidases and epithelial-mesenchymal transition-related proteins. In vivo experiments confirmed the inhibitory effect of LIPUS at 1.5 W/cm2 on tumor growth.

Although LIPUS induced cell apoptosis and inhibited cell proliferation, it also promoted the invasion and metastasis of HCC cells under certain conditions, which was related to the regulation of matrix metallopeptidases and epithelial-mesenchymal transition-related proteins.

The tumor microenvironment (TME) is characterized by a complex array of factors, including aerobic conditions, high glutathione (GSH) levels, acidic pH, and elevated hydrogen peroxide (H2O2) content, all of which promote cancer progression and contribute to poor prognosis. Fortunately, these challenges can be addressed using MnO2-based nanomaterials. In this study, we have designed and synthesized a Curcumin/MnO2@PLGA@4T1 cell membrane (CMP@4T1m) system aimed at remodelling the TME and enhancing sonodynamic immunotherapy for breast cancer. Through the homologous targeting ability of 4T1m, CMP@4T1m efficiently accumulates at the tumor site. Upon ultrasound irradiation, curcumin (Cur) acts as a sonosensitizer, generating cytotoxic reactive oxygen species (ROS) that induce immunogenic cell death (ICD), activate T-cell responses, and repolarize protumoral M2-like macrophages to antitumoral M1-like macrophages. In the TME, which is mildly acidic and enriched with GSH and H2O2, MnO2 not only oxidizes GSH to glutathione disulfide (GSSG) but also reacts with H2O2 and H+ to produce oxygen, alleviating hypoxia and significantly enhancing the sonodynamic immunotherapy effect. Additionally, Mn2+ generated during this process converts H2O2 into cytotoxic hydroxyl radicals (˙OH). This study thus lays the foundation for advancing cancer nanomedicine, offering a novel approach that integrates TME remodelling with sonodynamic immunotherapy.

Conventional periodontitis treatments can be superseded by sonodynamic therapy. In this study, a Zn(OH)F/CaF2 heterojunction was synthesized via a hydrothermal method, which exhibited good biocompatibility and antibacterial properties. The band gap decreased significantly after the formation of the heterojunction, thereby enhancing the internal electron transfer. In addition, after the bacteria contact with the material, the electrons of the electron transport chain turn to Zn(OH)F/CaF2 and affect its steady state. Ultimately, H2O2 in an inflammatory environment was used to react with Zn(OH)F/CaF2 to facilitate electron transfer under the influence of ultrasound, ultimately enhancing the catalytic activity. Zn(OH)F/CaF2 exhibits significant antibacterial efficacy against Porphyromonas gingivalis and Staphylococcus aureus. Trace elements Ca and Zn can promote tissue repair and osteogenic differentiation, resulting in less bone destruction and intact gingival tissue after periodontitis treatment. This sonodynamic therapy provides a rapid antibacterial, effective, and deep therapeutic method for treating periodontitis.

Breast cancer is the most commonly diagnosed cancer worldwide. Despite advancements in therapeutic modalities, its prognosis remains poor owing to complex clinical, pathological, and molecular characteristics. Sonodynamic therapy (SDT) is a promising approach for tumor elimination, using sonosensitizers that preferentially accumulate in tumor tissues and are activated by low-intensity ultrasound to produce reactive oxygen species. However, the clinical translation of SDT faces challenges, including the limited efficiency of sonosensitizers and resistance posed by the tumor microenvironment. The emergence of nanomedicine offers innovative strategies to address these obstacles. This review discusses strategies for enhancing the efficacy of SDT using sonosensitizers, including rational structural modifications, improved tumor-targeted enrichment, tumor microenvironment remodeling, and imaging-guided therapy. Additionally, SDT-based multimodal therapies, such as sono-chemotherapy, sono-immunotherapy, and sono-photodynamic therapy, and their potential applications in breast cancer treatment are summarized. The underlying mechanisms of SDT in breast cancer are briefly outlined. Finally, this review highlights current challenges and prospects for the clinical translation of SDT, providing insights into future advancements that may improve therapeutic outcomes for breast cancer.

Targeting the peculiarities of tumor tissue microenvironment different from normal tissue, such as lower pH and overexpression of hydrogen peroxide is the key to effective treatment. In this study, acid-responsive Z-scheme heterojunctions polyglycolated MoS2/CoFe2O4 (MoS2 = molybdenum disulfide, CoFe2O4 = cobalt ferrite) was synthesized using a two-step hydrothermal method, designated as MSCO-PEG, guided by dual modes of photoacoustic imagine (PAI) and nuclear magnetic imaging (MRI). MSCO-PEG (PEG = polyethylene glycol) responded to the acidic environment of tumor tissues and overexpression of hydrogen peroxide to turn on multimodal synergistic treatment of tumor cells under near-infrared-II (NIR-II) illumination. In particular, MSCO-PEG amplified the oxidizing ability of edge valence band holes (h+) and the reducing ability of conduction band electrons (e-) under NIR-II illumination through a "step-like" charge transfer mechanism, promoting the conversion of H2O to oxygen (O2) and the generation of superoxide radicals (O2-). In addition, the outstanding light absorption and photothermal conversion ability of MSCO made it have excellent photodynamic therapy (PDT) and photothermal therapy (PTT) effects. Meanwhile, the abundant multivalent metals endowed MSCO-PEG with the ability to generate chemodynamic therapy (CDT). MSCO-PEG's ability to clear glutathione (GSH) promotes tumor oxidative stress, increases reactive oxygen species (ROS) production, and enhances the synergistic therapeutic effect. This work provides a promising approach to advancing the clinical application of nanomaterials for anticancer therapy targeting the tumor microenvironment.

Theranostic nanosensitizers with combined near-infrared (NIR) fluorescence imaging and sono-photodynamic effects have great potential for use in the personalized treatment of deep-seated tumors. However, developing effective nanosensitizers for NIR fluorescence image-guided sono-photodynamic therapy remains a considerable challenge, including the low generation efficacy of reactive oxygen species (ROS), poor photostability, and the absence of cancer specificity. Herein, a novel heavy atom-free nanosensitizer is developed, which exhibits intense NIR fluorescence, high ROS generation efficiency, and improved aqueous stability. By conjugating a bulky and electron-rich group, 4-(1,2,2-triphenylvinyl)-1,1'-biphenyl (TPE), to the IR820 backbone, the resulting IR820 bearing TPE (IR820-TPE) effectively generates ROS via type I and II photochemical mechanisms under 808 nm laser irradiation. Moreover, TPE conjugation considerably increases the sono-photodynamic performance of IR820. To improve the intracellular delivery and tumor-targeting ability of IR820-TPE, biotin-conjugated exosome (B-Exo) is used as a natural nanocarrier. In vitro studies demonstrate the outstanding therapeutic performance of IR820-TPE-loaded B-Exo (IR820-TPE@B-Exo) in synergistic sono-photodynamic cancer therapy. In vivo studies reveal that IR820-TPE@B-Exo shows enhanced tumor accumulation, strong fluorescence signals, and effective sono-photodynamic therapeutic activity with high biosafety. This work demonstrates that IR820-TPE@B-Exo is a promising sono-phototheranostic agent for safe and targeted cancer therapy and NIR fluorescence imaging.

This study addresses the challenge of enhancing ferroptosis efficacy for tumor therapy, particularly the limited therapeutic efficiency of current inducers due to tumor microenvironment constraints. Herein, we developed a hollow ultrasound-triggered ZnFe2O4-Bi2MoO6 (ZB) S-scheme heterojunction loaded with artesunate (ART) to overcome these limitations. The ZB heterojunction with a particle size of ∼250 nm efficiently separates electron-hole pairs under ultrasound (US), promoting the generation of reactive oxygen species (ROS). The photodynamic effect of ZB further boosts ROS production, while ART, controlled-released by phase change materials under laser/US stimulation, enhances ROS production via Fe2+-mediated decomposition. This triple-enhanced strategy accumulates lipid peroxidation (LPO), significantly improving ferroptosis effects with a tumor suppression rate of 94.3 %. Moreover, ZB enables multimodal imaging and stimulates antitumor immunity, demonstrating its potential as a diagnostic and therapeutic agent. Our findings demonstrate the potential of this ZB@ART system in advancing ferroptosis-based tumor therapies, inspiring future designs of efficient ferroptosis inducers.

Despite the excellent advantages of biomicrorobots, such as autonomous navigation and targeting actuation, effective penetration and retention to deep lesion sites for effective therapy remains a longstanding challenge. Here, we present dual-engine cell microrobots, which we refer to as PR-robots, created by conjugating photosynthetic bacteria (PSB) with red blood cells (RBCs). The robots penetrate the tumor interior in swarms through combined hypoxic traction and ultrasound actuation (UA). The hypoxia-targeting ability of PSB induced PR-robot accumulation in the tumor region. Subsequently, programmable UA trapped the PR-robots to form bioswarms and traverse tissue obstacles, penetrating the tumor interior. The substantial influx of PR-robots into the tumor tissue promoted the formation of tumor-specific thrombus (TST). Finally, the PSB and TST synergistically improved the effect of photothermal therapy. Thus, these advantages of remote ultrasound control technology pave the way for various new therapies in practical biomedicine.

Despite the promise of sonodynamic therapy (SDT)-mediated immunotherapy, the anticancer efficacy of current sonosensitizers is greatly limited by the immunosuppressive tumor microenvironment (TME) and their inability to selectively respond to it. Herein, oxygen vacancy-rich MnO2@hydroxyapatite (Ca10(PO4)6(OH)2) core-shell nanospheres (denoted as Ov-MO@CPO) as an advanced TME-responsive sonosensitizer for sonodynamic immunotherapy is demonstrated. The Ov-MO@CPO maintains its structural integrity under neutral conditions but dissolves the pH-sensitive hydroxyapatite shell under acidic TME to release active oxygen vacancy-rich MnO2 core, which reinvigorates H2O2 consumption and hypoxia alleviation due to its catalase-like activity. Furthermore, the introduced oxygen vacancies optimize the electronic structure of Ov-MO@CPO, with active electronic states near the Fermi level and higher d-band center. It results in accelerated electron-hole pair separation and lower catalytic energy barriers to boost ultrasound (US)-initiated ROS production. These multimodal synergistic effects effectively reverse the immunosuppressive tumor microenvironment, inhibiting tumor growth and metastasis in 4T1 tumor-bearing mice. No evident toxic effects are observed in normal mouse tissues. Additionally, when combined with an immune checkpoint inhibitor, Ov-MO@CPO-mediated SDT further improves the effectiveness of immunotherapy. This work affords a new avenue for developing TME-dependent sonosensitizers for SDT-mediated immunotherapy.

The inadequate generation of reactive oxygen species (ROS) and metastasis of malignant tumors are critical factors that limit the efficacy of conventional sonodynamic therapy in cancer treatment. Herein, an engineered piezocatalyst: cholesterol oxidase (CHO)-loaded Pt-ZnO nanoparticles (Pt-ZnO/CHO) that can explosively generate large amounts of ROS and block the metastasis of tumor, is developed for improving piezocatalytic tumor therapy. In this process, Pt-ZnO can substantially generate ROS via initiating ultrasound (US)-triggered piezocatalytic reactions. In situ-grown Pt nanoparticles not only optimize piezocatalytic activities but also facilitate oxygen (O2) production, thereby synergistically boosting ROS generation. Moreover, O2 produced by Pt-ZnO can accelerate the depletion of excess cholesterol in tumor cells under CHO catalysis to disrupt the integrity of lipid rafts and inhibit the formation of lamellipodia, significantly suppressing the proliferation and metastasis of tumor cells. This strategy by promoting ROS generation and blocking the metastatic pathway of cancer cells offers a new idea for enhanced efficacy-oriented cancer therapeutic strategies.

Cuproptosis, a novel approach utilizing copper carriers to trigger programmed cell death, exhibits promise for enhancing traditional therapies and activating robust adaptive immune responses. However, the uncontrolled release of Cu ions risks triggering cuproptosis in healthy tissues, potentially causing irreversible damage. To address this, we report on the use of a Cu-MOF (copper metal-organic framework) protective layer to regulate the biodegradation of copper-based nanomaterials. In situ formation of Cu-MOF on Cu2O nanocubes not only stabilizes the material under physiological conditions but also enhances its sonodynamic therapy (SDT) capabilities by establishing a Z-Scheme heterojunction. Upon SDT activation, the targeted Cu ion release at the tumor site triggers a cascade of reactions, generating reactive oxygen species (ROS) via Fenton-like processes and depleting glutathione (GSH). This ROS surge, combined with effective cuproptosis, modulates the immunosuppressive tumor microenvironment, inducing immunogenic cell death to eliminate primary tumors and inhibit metastasis. This study offers a new paradigm for the controlled integration of SDT, chemodynamic therapy (CDT), cuproptosis, and immunotherapy, achieving precise tumor-targeted treatment via controlled copper nanomaterial degradation.

Recent common clinical treatments for implant bacterial infections involve replacing inert implants and using antibiotics. However, these methods remain limited in their effectiveness for pathogen clearance, immune regulation, and osteogenesis. In this study, we developed a Zr-doped heterointerface of SrTiO3 and Hap (SrTiZrO3/Hap) heterojunction coating with single-atom Zr doping and heterogeneous interfaces designed for ultrasound-responsive antimicrobial activity and bone formation. Under ultrasound, the mechanical force exerted by SrTiZrO3/Hap enhances its physical puncture and sonodynamic activity, synergizing with the metalloimmunotherapy effect of Zr4+ for efficient antimicrobial activity. The primary mechanism enhancing sonodynamic activity involves local interfacial polarization from single-atom Zr doping, achieving piezoelectric catalysis in conjunction with electronic polarization from the built-in electric field. SrTiZrO3/Hap achieved a 99.3% antibacterial rate against S. aureus and 99.7% against E. coli under ultrasound. Additionally, SrTiZrO3/Hap promoted osteogenic differentiation after ultrasound irradiation by activating the PI3K/Akt pathway via its piezoelectric, needle-like topological surface and the release of functional ions, thus accelerating bone repair.

Sonodynamic therapy (SDT) is a promising cancer treatment known for its deep tumor penetration and high efficacy. However, developing highly efficient sonosensitizers remains a significant challenge. Reports on SDT using aggregation-induced emission luminogens (AIEgens) are rare, highlighting the urgent need for novel AIE-active sonosensitizers. For the first time, we have developed tumor- and macrophage-targeting nano micelles, AIE/Biotin/Mannose-M (ABM-M), utilizing aggregation-induced emission polymers. The ABM-M mediate immunogenic cell death through SDT. By reprogramming tumor-associated macrophages (TAMs), they promote the conversion of M2 macrophages into M1 macrophages, reversing the tumor's immunosuppressive environment. We optimized the ratio of functional molecules to achieve maximum fluorescence intensity and reactive oxygen species (ROS) generation. The multi-targeting nature of ABM-M enables them to bind to relevant antibodies or other molecules, enhancing the capture and presentation of tumor antigens. This, in turn, activates the immune responses of dendritic cells and T cells while inhibiting angiogenesis, creating a more favorable microenvironment for antitumor therapy. Furthermore, ABM-M can be combined with immune checkpoint inhibitors, such as anti-PD-L1 antibodies, to achieve promising outcomes in cancer immunotherapy. The ABM-M nanomaterials offer multi-layered and multi-targeting immune regulation. This study provides a blueprint for developing next-generation cancer diagnostic and therapeutic strategies. STATEMENT OF SIGNIFICANCE: Our research pioneers the use of nanomicelles to simultaneously target both tumor cells and tumor-associated macrophages (TAMs), integrated with sonodynamic therapy. Through precise ratio adjustments, we engineered nanomicelles capable of multi-target regulation. These micelles uniquely induce immunogenic cell death (ICD) and repolarize macrophages from an immunosuppressive M2 phenotype to an immunostimulatory M1 phenotype, reversing the tumor's immunosuppressive microenvironment. This dual mechanism can be enhanced by combining with immune checkpoint inhibitors, such as anti-PD-L1 antibodies, offering a promising strategy to treat refractory cancers. Extensive in vitro and in vivo validation confirms their therapeutic potential, providing a solid foundation for clinical application. This innovative approach shows significant promise for revolutionizing cancer treatment and improving patient outcomes.

As a kind of mechanical wave, ultrasound has been widely employed in the biomedical field due to its superiors of deep tissue penetration, non-destructiveness and non-toxicity. In this review, we highlight current progress and prospects in using ultrasound as a powerful tool for disease treatment and medical imaging, including (1) ultrasound as energy input for driving nano/micromotor in drug delivery, this part first introduces the synthesis and motion behavior of nano/micromotors, then reviews the small molecular and macromolecular compounds that the nano/micromotors are delivering; (2) sonosensitive nanomaterials for disease therapy, the sonodynamic, sonopiezoelectric, sonothermal, and sonomechanical therapy will all be covered; (3) ultrasound as a non-invasive technique for nano/micromotor tracking or medical imaging; (4) the sonoporation of nano/microbubble. Future challenges in using ultrasound for disease treatment or medical imaging will also be described in the conclusion part.

Ultrasound-mediated reactive oxygen species (ROS) generation is pivotal in specifically inducing pyroptosis of tumor cells. However, the effectiveness of pyroptosis is generally hindered by the constraints of ROS generation efficiency. Herein, a new porphyrin-based metal-organic framework (Fe(TCPP)-MOF) was rationally designed via an innovative dual-solvent strategy to amplify ROS generation for ultrasound-controlled pyroptosis. The crystal structure of Fe(TCPP)-MOF was elucidated by continuous rotation electron diffraction technique, revealing its regular and rigid conformation. The porphyrin molecules were precisely oriented and firmly confined within the scaffold, effectively restricting intramolecular motion. The ample distance of 6.8 Å between two porphyrin molecules, combined with the interaction region indicator visualization, confirmed the absence of π-π stacking interactions in the Fe(TCPP)-MOF framework, thereby avoiding the aggregation-caused quenching effect. Furthermore, the permanent porosity and expansive surface area of Fe(TCPP)-MOF enhanced its interaction with oxygen. These ingenious structural features endowed Fe(TCPP)-MOF with a unique ability to generate a large amount of singlet oxygen under ultrasound activation. Meanwhile, the impetus of ultrasound also accelerated the rate of the Fenton reaction catalyzed by iron ions, significantly boosting the generation of hydroxyl radicals. Benefiting from the dual amplification of ROS, Fe(TCPP)-MOF could efficiently induce tumor cells pyroptosis under ultrasound stimulation, thereby intensifying the potency of cancer immunotherapy.

Lipid nanoparticles (LNPs) based messenger RNA (mRNA) therapeutics hold immense promise for treating a wide array of diseases, while their nonhepatic organs targeting and insufficient endosomal escape efficiency remain challenges. For LNPs, polyethylene glycol (PEG) lipids have a crucial role in stabilizing them in aqueous medium, but they severely hinder cellular uptake and reduce transfection efficiency. In this study, we designed ultrasound (US)-assisted fluorinated PEGylated LNPs (F-LNPs) to enhance spleen-targeted mRNA delivery and transfection. Through liquid-to-gas phase transition, we enabled the controlled shedding of fluorinated PEG lipids from F-LNPs, facilitating cellular uptake, membrane fusion, and mRNA release. In vivo results demonstrated that US-assisted F-LNPs increased mRNA transfection approximately 4.0-fold in the spleen following intravenous administration. Notably, the F-LNPs achieved effective mRNA delivery to antigen-presenting cell subsets, such as dendritic cells, macrophages, and B cells. The targeted delivery of full-length ovalbumin-encoding mRNA vaccine induced significant CD8+ T cell response and exhibited excellent therapeutic effect against the ovalbumin-transduced B16F10 tumor model. These findings establish a novel strategy for spleen-specific mRNA delivery through the combination of fluorinated PEG lipids and US treatment, which holds substantial promise for enhancing the efficacy of immunotherapy, potentially broadening the scope of clinical applications for mRNA-based therapy.

Sterile and infection-associated inflammatory diseases are becoming increasingly prevalent worldwide. Conventional drug therapies often entail significant drawbacks, such as the risk of drug overdose, the development of drug resistance in pathogens, and systemic adverse reactions, all of which can undermine the effectiveness of treatments for these conditions. Nanomaterials (NMs) have emerged as a promising tool in the treatment of inflammatory diseases due to their precise targeting capabilities, tunable characteristics, and responsiveness to external stimuli. Ultrasound (US), a non-invasive and effective treatment method, has been explored in combination with NMs to achieve enhanced therapeutic outcomes. This review provides a comprehensive overview of the recent advances in the use of US-mediated NMs for treating inflammatory diseases. A comprehensive introduction to the application and classification of US was first presented, emphasizing the advantages of US-mediated NMs and the mechanisms through which US and NMs interact to enhance anti-inflammatory therapy. Subsequently, specific applications of US-mediated NMs in sterile and infection-associated inflammation were summarized. Finally, the challenges and prospects of US-mediated NMs in clinical translation were discussed, along with an outline of future research directions. This review aims to provide insights to guide the development and improvement of US-mediated NMs for more effective therapeutic interventions in inflammatory diseases.

Sonodynamic therapy (SDT) represents a promising approach for cancer treatment. Compared to photodynamic therapy, SDT offers increased penetration depth and higher precision. However, the practical application of SDT is constrained by the low water solubility, poor tumor specificity, and metabolic susceptibility of most sonosensitizers. Recent research has explored the use of piezoelectric materials as sonosensitizers in cancer treatment and inhibition of bacterial growth. Upon ultrasound excitation, the separation of electron-hole (e--h+) pairs occurs within the piezoelectric material. By improving the crystal structure of the material or incorporating other nanoparticles to prevent rapid recombination of e--h+ pairs, the piezoelectric material accumulates charges in the conduction band and valence band, achieving the redox potential of O2/·O2 -. This enables the piezoelectric material to serve as a sonosensitizer, leading to the concept termed Sono-Piezo Dynamic Therapy (SPDT). This review aims to define the concept of SPDT, provide a systematic overview of the historical development of piezoelectric materials in the application of SDT, and elucidate the potential mechanisms by which piezoelectric materials act as sonosensitizers. Importantly, various piezoelectric materials will be discussed in terms of their feasibility, advantages, and disadvantages as sonosensitizers, offering new perspectives for identifying potential sonosensitizers.

Reactive oxygen species (ROS) play a crucial role in the pathogenesis of cancer. Non-invasive therapies that promote intracellular ROS generation, including photodynamic therapy (PDT), sonodynamic therapy (SDT), and chemodynamic therapy (CDT), have emerged as novel approaches for cancer treatment. These therapies directly kill tumor cells by generating ROS, and although they show great promise in tumor treatment, many challenges remain to be addressed in practical applications. Firstly, the inherent complexity of the tumor microenvironment (TME), such as hypoxia and elevated glutathione (GSH) levels, hinders ROS generation, thereby significantly diminishing the efficacy of ROS-based therapies. In addition, these therapies are influenced by their intrinsic mechanisms. To overcome these limitations, various nanoparticle (NP) systems have been developed to improve the therapeutic efficacy of non-invasive therapies against tumors. This review first summarizes the mechanisms of ROS generation for each non-invasive therapy and their current limitations, with a particular focus on the enhancement strategies for each therapy based on NP systems. Additionally, various strategies to modulate the TME are highlighted. These strategies aim to amplify ROS generation in non-invasive therapies and enhance their anti-tumor efficiency. Finally, the current challenges and possible solutions for the clinical translation of ROS-based non-invasive therapies are also discussed.

Drug-resistant bacteria infected wounds often bring high risks of delayed healing process and even death. Sonodynamic therapy (SDT) can efficiently kill drug-resistant bacteria. However, superabundant reactive oxygen species (ROS) generated during SDT inevitably trigger significant inflammatory responses, hindering tissue remodeling. Herein, we develop intelligent ultrathin high-entropy hydrotalcites (UHE-HTs)-based injectable thermal-responsive hydrogel loaded with nicotinamide mononucleotide (UHE-HTs/PFN), aiming to achieve programmed antibacterial and anti-inflammatory effects. In the early infection stage, sonosensitive UHE-HTs/PFN hydrogel simultaneously can trigger rapid production of singlet oxygen (1O2) under ultrasound and efficient MDR bacterial sterilization. After halting ultrasonic irradiation, oxidoreductase-mimicking catalysis and nicotinamide mononucleotide release of UHE-HTs/PFN hydrogel effectively reduce ROS levels at wound sites, dampening the NF-κB inflammatory pathway. Such inhibited NF-κB expression can not only reduce the production of pro-inflammatory cytokines and inflammatory responses, but also significantly down-regulate the pyroptosis pathways (NLRP3/ASC/Casp-1) and inhibit pyroptosis that leads to inflammation. Moreover, significantly reduced ROS levels and synergistic release of Mg2+ reverse pro-inflammatory immune microenvironment. Both in vitro and in vivo assays demonstrate that UHE-HTs/PFN hydrogel can transform the adverse infected wound environment into a regenerative one by eradicating drug-resistant bacteria, scavenging ROS, and synergistic anti-inflammation. Therefore, this work develop an intelligent UHE-HTs/PFN hydrogel act as a "lever" that effectively achieve a balance between ROS generation and annihilation, rebuilding harmonious bactericidal and anti-inflammatory effects to remedy drug-resistant bacteria infected wound.

Ferroptosis plays a significant role in overcoming the therapeutic resistance of cancer cells. Herein, a carrier-free nanoparticle based on small molecule drug sorafenib (SRF) and sonosensitizer rose bengal (RB) was constructed (named SR NPs) for ferroptosis-driven chemotherapy and sonodynamic synergistic therapy (SDT) of prostate cancer (PCa). SR NPs could be enriched in tumor cells and efficiently inhibit tumor cell proliferation. These nanodrugs could significantly reduce glutathione (GSH) synthesis, and inhibit glutathione peroxidase 4 (GPX4) expression by inhibiting the glutamate/cysteine antiporter system (System Xc-) pathway of ferroptosis. Moreover, SR NPs-mediated ferroptosis significantly improved the amount of reactive oxygen species (ROS) generated by SDT, inhibited cell migration and adhesion, enhanced the accumulation of lipid peroxides (LPO) and augmented chemo-sonodynamic therapy. Notably, in vivo studies demonstrated that SR NPs enhanced tumor accumulation, exhibited good biocompatibility, and showed high anti-tumor efficacy in PC-3 tumor-bearing mice. This work offered a new strategy to enhance the treatment efficacy of prostate cancer (PCa) through ferroptosis-chemotherapy-sonodynamic synergistic therapy.

Medical catheters are susceptible to biological contamination and pathogen invasion, leading to infection and inflammatory complications. The development of antimicrobial coatings for medical devices has emerged as a promising strategy. However, limited biological functionality and the incompatibility between bactericidal properties and biosafety remain great challenges. Herein, a multifunctional polymer coating (CPB-Ac) is created, incorporating an ultrasonic-responsive carbon monoxide release unit (CORM-Ac) and antifouling unit to treat catheter-related complications. As-synthesized CPB-Ac polymer can be stably anchored to various medical devices with arbitrary shapes and compositions via facile UV treatment. Both in vivo and vitro experiments demonstrated that this multi-functional coating exhibits anti-fouling, anti-inflammatory, and broad-spectrum antibacterial activities as well as good biosafety. During the initial implantation phase, the antifouling units of CPB-Ac coating effectively inhibit the attachment of biological contaminants, significantly reducing the risk of thrombosis and bacterial infection. Once bacterial infection occurs, ultrasonic irradiation can activate CPB-Ac coating to release CO with a much higher amount of 55.3 µm than non-ultrasound controls, therefore rapidly eliminating bacteria and alleviating inflammatory response. It is believed that the work may provide an effective method for the development of next-generation intelligent medical coatings against catheter-related complications.

Piezoelectric catalysis for tumor treatment is an emerging method for generating reactive oxygen species (ROS). However, the development and optimization of piezoelectric catalytic nanomaterials remain the major challenge. Herein, by regulating the internal and surface defects of graphene phase carbon nitride (defect-engineered g-C3N4), its piezoelectricity and sonocatalytic performance is enhanced, thus achieving efficient tumor treatment. By reducing bulk defects, the charges excited by ultrasound (US) within the defect-engineered g-C3N4 can migrate more rapidly to the material surface, thereby enhancing their participation in redox reactions. Increasing surface defects not only introduce more active sites on the surface of defect-engineered g-C3N4 but also enhance the asymmetry of the defect-engineered g-C3N4 structure, resulting in excellent piezoelectric properties. This defect-engineered g-C3N4 nanosheet can effectively generate ROS in tumor cells and induce tumor cell apoptosis under US stimulation. This work not only introduces a method to enhance the piezoelectric catalytic performance of g-C3N4 but also expands the potential application of defect-engineered piezoelectric materials to tumor treatment.