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Abstract Owing to the high penetration ability and the safety of ultrasound (US) of sonodynamic therapy (SDT), it has gained significant attention in tumor treatment. However, its therapeutic efficiency depends on the performance of the sonosensitizers. The hypoxic microenvironment and abnormal stromal matrix restrict the full potential of sonosensitizers. In this study, a US‐activated bowl‐shaped nanobomb (APBN) is designed as a novel sonosensitizer to enhance the SDT effect through various means. This enhancement strategy combines three major characteristics: relieving tumor hypoxia, amplifying bubble cavitation damage, and US‐movement‐enhanced permeation. The unique bowl‐shaped structure of APBN provides more favorable attachment sites for the generated oxygen gas bubbles. Thus, when catalase‐like APBN catalyzes endogenous hydrogen peroxide to produce oxygen, bubbles accumulate at the groove, preventing the dissipation of oxygen and increasing the number of cavitation nuclei to improve the acoustic cavitation effect. This approach differs from traditional SDT strategies because it couples the sonodynamic effect with reactive oxygen species generation and bubble cavitation damage rather than a single action. Additionally, the asymmetric bowl‐shaped structure generates a driving force under the US field, improving the distribution of sonosensitizers in the tumors. Using US and photoacoustic imaging for dual localization, these sonosensitizers can improve the accuracy of orthotopic liver tumor treatment, which presents a promising avenue for the treatment of deep tumors.

The growing pace of two-dimensional (2D) transitional metal carbides and nitrides (MXenes) has become a spotlight for recent research. Similarly, the need to close the gap left by conventional antibiotics, fighting off bacterial infections, and drug resistance has become eminent. Especially, MXenes are widely used as excellent photothermal agents. However, there are limited reports on MXenes as sonosensitizer. Herein, a high-entropy MXene (HEM), TVNMC was fabricated for the generation of reactive oxide species (ROS) against Methicillin-resistance Staphylococcus aureus (MRSA). Interestingly the energy storage and conversion from the diverse composition of the TVNMC MXenes allowed the generation of ROS under US irradiation and even enhanced under Photothermal therapy. This combinatorial therapy undertook a near-total kill and eradication of MRSA with its biofilm. Moreover, TVNMC MXene simultaneously eliminated MRSA abscesses while promoting wound healing with negligible anomaly to murine tissues under sonodynamic and photothermal therapy, making the TVNMC MXene a promising sonosensitizer for possible biomedical usage. Overall, this system provides great potential for the use of high-entropy MXenes as a new type of sonosensitizer in anti-infection therapy.

Lung cancer is the deadliest kind of cancer in the world, and the hypoxic tumor microenvironment can significantly lower the sensitivity of chemotherapeutic drugs and limit the efficacy of different therapeutic approaches. In order to overcome these problems, we have designed a drug-loaded targeted DNA nanoflowers encoding AS1411 aptamer and encapsulating chemotherapeutic drug doxorubicin and oxygen-producing drug horseradish peroxidase (DOX/HRP-DFs). These nanoflowers can release drugs in response to acidic tumor microenvironment and alleviate tumor tissue hypoxia, enhancing the therapeutic effects of chemotherapy synergistic with sonodynamic therapy. Owing to the encoded drug-loading sequence, the doxorubicin loading rate of DNA nanoflowers reached 73.24 ± 3.45%, and the drug could be released quickly by disintegrating in an acidic environment. Furthermore, the AS1411 aptamer endowed DNA nanoflowers with exceptional tumor targeting properties, which increased the concentration of chemotherapeutic drug doxorubicin in tumor cells. It is noteworthy that both in vitro and in vivo experiments demonstrated DNA nanoflowers could considerably improve the hypoxia of tumor cells, which enabled the generation of sufficient reactive oxygen species in combination with ultrasound, significantly enhancing the therapeutic effect of sonodynamic therapy and evidently inhibiting tumor growth and metastasis. Overall, this DNA nanoflowers delivery system offers a promising approach for treating lung cancer.

Min Yang,1,2 Mengyao Xie,1,2 Jiajun Guo,1,2 Yuqing Zhang,1,2 Yan Qiu,1,2 Zhibiao Wang,1,2 Yonghong Du1,2 1State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 2Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, People’s Republic of ChinaCorrespondence: Zhibiao Wang; Yonghong Du, State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, People’s Republic of China, Tel/Fax +86-23-68485000 ; +86-23-68485021, Email wangzb@cqmu.edu.cn; duyonghong@cqmu.edu.cnBackground: Candida albicans (C. albicans) forms pathogenic biofilms, and the dense mucus layer secreted by the epithelium is a major barrier to the traditional antibiotic treatment of mucosa-associated C. albicans infections. Herein, we report a novel anti-biofilm strategy of mucus-permeable sonodynamic therapy (mp-SDT) based on ultrasound (US)-mediated amphotericin B-loaded PEGylated PLGA nanoparticles (AmB-NPs) to overcome mucus barrier and enable the eradication of C. albicans biofilm.Methods: AmB-NPs were fabricated using ultrasonic double emulsion method, and their physicochemical and sonodynamic properties were determined. The mucus and biofilm permeability of US-mediated AmB-NPs were further investigated. Moreover, the anti-biofilm effect of US-mediated AmB-NPs treatment was thoroughly evaluated on mucus barrier abiotic biofilm, epithelium-associated biotic biofilm, and C. albicans-induced rabbit vaginal biofilms model. In addition, the ultrastructure and secreted cytokines of epithelial cells and the polarization of macrophages were analyzed to investigate the regulation of local cellular immune function by US-mediated AmB-NPs treatment.Results: Polymeric AmB-NPs display excellent sonodynamic performance with massive singlet oxygen (1O2) generation. US-mediated AmB-NPs could rapidly transport through mucus and promote permeability in biofilms, which exhibited excellent eradicating ability to C. albicans biofilms. Furthermore, in the vaginal epithelial cells (VECs)-associated C. albicans biofilm model, the mp-SDT scheme showed the strongest biofilm eradication effect, with up to 98% biofilm re-formation inhibition rate, improved the ultrastructural damage, promoted local immune defense enhancement of VECs, and regulated the polarization of macrophages to the M1 phenotype to enhance macrophage-associated antifungal immune responses. In addition, mp-SDT treatment exhibited excellent therapeutic efficacy against C. albicans-induced rabbit vaginitis, promoted the recovery of mucosal epithelial ultrastructure, and contributed to the reshaping of a healthier vaginal microbiome.Conclusion: The synergistic anti-biofilm strategies of mp-SDT effectively eradicated C. albicans biofilm and simultaneously regulated local antifungal immunity enhancement, which may provide a new approach to treat refractory drug-resistant biofilm-associated mucosal candidiasis.Keywords: C. albicans biofilm, PEGylated nanoparticles, mucus penetration, sonodynamic therapy

Huimin Tian, Haitao Shang, Yichi Chen, Bolin Wu, Chunyue Wang, Xiaodong Wang, Wen Cheng Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of ChinaCorrespondence: Wen Cheng, Department of Ultrasound, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin, Heilongjiang Province, 150081, People’s Republic of China, Tel +86 13313677182, Fax +86 451 85718392, Email hrbchengwen@163.comBackground: Apoptosis resistance of hepatocellular carcinoma (HCC) often leads to treatment failure. Nonetheless, overcoming the resistance of HCC to apoptosis by inducing necroptosis of tumor cells to bypass the apoptotic pathway may be a promising treatment strategy. Sonodynamic therapy (SDT) has broad prospects in disease treatment because of its noninvasive characteristic and spatiotemporal control. The combination of SDT and shikonin in the treatment of HCC is expected to be a new tumor treatment method that can overcome apoptosis resistance.Methods: In this study, the antitumor effect was evaluated using normal liver cell line WRL68, HCC cell line HepG2 and HepG2 xenograft mouse models. Indocyanine green (ICG) was loaded on nanobubbles (NBs) to construct ICG-loaded nanobubbles (ICG-NBs). Combined sonosensitizer nanoplatforms with ultrasound (US) to achieve efficient SDT, the combination of SDT and shikonin in treating HCC can activate shikonin-induced necroptosis. As a result, tumor cells that produced apoptosis resistance were destroyed by necroptosis.Results: The results indicated a successful preparation of ICG-NBs with a uniform particle size of 273.0 ± 118.9 nm spherical structures. ICG-NB-mediated SDT, in combination with shikonin treatment, inhibited the viability, invasion, and migration of tumor cells. SDT + shikonin treatment group caused a substantial increase in necroptotic cells. The increased degree of tumor necrosis and the upregulated expression of receptor-interacting protein 3 kinase were observed in vivo studies, which indicated that the antitumor effect was accompanied by enhanced necroptosis in the SDT + shikonin treatment group.Conclusion: ICG-NB-mediated SDT combined with shikonin inhibits the growth of HCC by increasing the necroptosis of tumor cells. Therefore, this combination therapy is a promising treatment strategy against the specific cancer.Keywords: sonodynamic therapy, hepatocellular carcinoma, necroptosis, shikonin, sonosensitizer

Jia-Rui Du, Deng-Ke Teng, Yang Wang, Qimeihui Wang, Yuan-Qiang Lin, Qiang Luo, Jia-Nan Xue, Ling-Yu Zhu, Peng Dong, Gen-Mao Zhang, Yan Liu, Zhi-Xia Sun, Hui Wang,* Guo-Qing Sui* Department of Ultrasound, China-Japan Union Hospital of Jilin University, Changchun, Jilin, 130000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hui Wang; Guo-Qing Sui, Email whui66@jlu.edu.cn; suiguoqing@jlu.edu.cnPurpose: Sonodynamic therapy (SDT), with its high tissue penetration and noninvasive advantages, represents an emerging approach to eradicating solid tumors. However, the outcomes of SDT are typically hampered by the low oxygen content and immunosuppression in the tumor microenvironment (TME). Accordingly, we constructed a cascade nanoplatform to regulate the TME and improve the anti-tumor efficiency of SDT.Methods: In this study, we rationally design cascade nanoplatform by incorporating immunostimulant hyaluronic acid (HA) and sonosensitizer chlorin e6 (Ce6) on the polydopamine nanocarrier that is pre-doped with platinum nanozymes (designated Ce6/Pt@PDA-HA, PPCH).Results: The cascade reactions of PPCH are evidenced by the results that HA exhibits reversing immunosuppressive that converts M2 macrophages into M1 macrophages in situ, while producing H2O2, and then platinum nanozymes further catalyze the H2O2 to produce O2, and O2 produces abundant singlet oxygen (1O2) under the action of Ce6 and low-intensity focused ultrasound (LIFU), resulting in a domino effect and further amplifying the efficacy of SDT. Due to its pH responsiveness and mitochondrial targeting, PPCH effectively accumulates in tumor cells. Under LIFU irradiation, PPCH effectively reverses immunosuppression, alleviates hypoxia in the TME, enhances reactive oxygen species (ROS) generation, and enhances SDT efficacy for eliminating tumor cells in vivo and in vitro. Meanwhile, an in vivo dual-modal imaging including fluorescence and photoacoustic imaging achieves precise tumor diagnosis.Conclusion: This cascade nanoplatform will provide a promising strategy for enhancing SDT eradication against tumors by modulating immunosuppression and relieving hypoxia.Keywords: tumor microenvironment, tumor-associated macrophages, cascade reactions, sonodynamic therapy, tumor hypoxia

Xiaodong Wang, Chunyue Wang, Huimin Tian, Yichi Chen, Bolin Wu, Wen Cheng Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of ChinaCorrespondence: Wen Cheng; Bolin Wu, Department of Ultrasound, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin, 150081, People’s Republic of China, Tel +86 13313677182 ; +86 15663615088, Email chengwen@hrbmu.edu.cn; wubolin@hrbmu.edu.cnPurpose: Sonodynamic therapy (SDT) is a promising and significant measure for the treatment of tumors. However, the internal situation of hepatocellular carcinoma (HCC) is complex, separate SDT treatment is difficult to play a good therapeutic effect. Here, we used SDT combined with MG-132 to mediate apoptosis and autophagy of HCC cells to achieve the purpose of treatment of cancer.Methods: To determine the generated reactive oxygen species (ROS) and the change of mitochondrial membrane potential (ΔΨm), HepG2 cells were stained by 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA) and 5,5′,6,6′-Tetrachloro-1,1′,3,3′-tetraethyl-imidacarbocyanine iodide (JC-1) staining to determine the IR-820@NBs-mediated SDT to achieve HCC therapy through the mitochondrial pathway. Cell counting kit 8 (CCK-8) assay and flow cytometry were used to detect cell viability and apoptosis rate of HepG2 cells. Autophagy was detected by mCherry-GFP-LC3B fluorescence labeling. Chloroquine (Cq) pretreatment was used to explore the relationship between autophagy and apoptosis. To detect the ability of HepG2 cells migration and invasion, cell scratch assay and transwell assay were used.Results: The successfully prepared IR-820@NBs could effectively overcome the shortcomings of IR-820 and induce lethal levels of ROS by ultrasound irradiation. As a dual agonist of apoptosis and autophagy, MG-132 could effectively enhance the efficacy of SDT in the process of treating HCC. After pre-treatment with Cq, the cell activity increased and the level of apoptosis decreased, which proved that apoptosis and autophagy were induced by combined therapy, autophagy, and apoptosis have the synergistic anti-tumor effect, and part of apoptosis was autophagy-dependent. After combined therapy, the activity and invasive ability of HCC cells decreased significantly.Conclusion: SDT combined with MG-132 in the process of treating liver cancer could effectively induce apoptosis and autophagy anti-tumor therapy, which is helpful to the research of new methods to treat liver cancer.Keywords: sonodynamic therapy, MG-132, apoptosis, autophagy, hepatocellular carcinoma

Can Hu,1,2,* Yan Qiu,1,2,* Jiajun Guo,1,2 Yuchao Cao,1,2 Dairong Li,3 Yonghong Du1,2 1State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 2Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dairong Li, Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Chongqing Medical University, No. 1, Youyi Road, Yuzhong District, Chongqing, 400016, People’s Republic of China, Tel +86-23-89012745, Fax +86-23-68485021, Email lidairong@hospital.cqmu.edu.cn Yonghong Du, State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, No. 1, Yixueyuan Road, Yuzhong District, Chongqing, 400016, People’s Republic of China, Tel/Fax +86-23-68485021, Email duyonghong@cqmu.edu.cnPurpose: Tuberculosis (TB) is a chronic disease caused by Mycobacterium tuberculosis (MTB) that remains a major global health challenge. One of the main obstacles to effective treatment is the heterogeneous microenvironment of TB granulomas. This study aimed to investigate the potential of a hypoxic remission-based strategy to enhance the outcome of tuberculosis treatment when implemented in combination with ultrasound.Methods: A PLGA nanoparticle (LEV@CAT-NPs) loaded with levofloxacin (LEV) and catalase (CAT) was fabricated by a double emulsification method, and its physical characteristics, oxygen production capacity, drug release capacity, and biosafety were thoroughly investigated. The synergistic therapeutic effects of ultrasound (US)-mediated LEV@CAT-NPs were evaluated using an experimental mouse model of subcutaneous tuberculosis granuloma induced by Bacille Calmette-Guérin (BCG) as a substitute for MTB.Results: LEV@CAT-NPs exhibited excellent oxygen production capacity, biosafety, and biocompatibility. Histological analysis revealed that ultrasound-mediated LEV@CAT-NPs could effectively remove bacteria from tuberculous granulomas, significantly alleviate the hypoxia state, reduce the necrotic area and inflammatory cells within the granuloma, and increase the penetration of dyes in granuloma tissues. The combined treatment also reduced the serum levels of inflammatory cytokines (eg, TNF-α, IL-6, and IL-8), and significantly downregulated the expression of hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF). These results suggested that the synergistic treatment of ultrasound-mediated LEV@CAT-NPs effectively eradicated the bacterial infection and reversed the hypoxic microenvironment of tuberculous granulomas, further promoting tissue repair.Conclusion: This study provides a non-invasive and new avenue for treating refractory tuberculosis infections. The potential role of regulating hypoxia within infected lesions as a therapeutic target for infection deserves further exploration in future studies.Keywords: tuberculosis granulomatous, hypoxia, catalase, sonodynamic therapy, Bacille Calmette-Guérin

Photothermal, photodynamic and sonodynamic cancer therapies offer opportunities for precise tumor ablation and reduce side effects. The cyclic guanylate adenylate synthase-stimulator of interferon genes (cGAS-STING) pathway has been considered a potential target to stimulate the immune system in patients and achieve a sustained immune response. Combining photothermal, photodynamic and sonodynamic therapies with cGAS-STING agonists represents a newly developed cancer treatment demonstrating noticeable innovation in its impact on the immune system. Recent reviews have concentrated on diverse materials and their function in cancer therapy. In this review, we focus on the molecular mechanism of photothermal, photodynamic and sonodynamic cancer therapies and the connected role of cGAS-STING agonists in treating cancer.

Yang M, Xie M, Guo J, et al. Int J Nanomedicine. 2023;18:7941-7963. We, the Editor and Publisher of the journal International Journal of Nanomedicine are retracting the published article. Following publication of the article, the authors raised concerns about the duplication of images from Figures 2, 6, 9, 11 and 12. Specifically, The image for Figure 2A, SEM image of AmB-NPs, has been duplicated with the image for Figure 3B, SEM image of BM2-LVFX-NPs, from Li G, Li J, Hou Y, et al. Levofloxacin-Loaded Nanosonosensitizer as a Highly Efficient Therapy for Bacillus Calmette-Guérin Infections Based on Bacteria-Specific Labeling and Sonotheranostic Strategy. Int J Nanomedicine. 2021;16:6553-6573. https://doi.org/10.2147/IJN.S321631. Images for Figure 6C, AmB-NPs and US+AmB have been duplicated but show a different colour intensity. Images for Figure 9C, Control and US, have been duplicated. Images for Figure 11C, C. albicans CD86, AmB and IL-4 CD206, AmB-NPs, have been duplicated. Images for Figure 11C, C. albicans CD86, US+AmB-NPs and IL-4 CD206, US, have been duplicated but show a different immunofluorescene staining intensity. Images for Figure 12C, AmB and US+AmB, have been duplicated but one of the images has been flipped. Images for Figure 12D, US+AmB and US+AmB-NPs, have been duplicated. The authors were cooperative and responded to our queries but were unable to provide a satisfactory explanation for the duplicated images but did provide some original data for the study. However, as verifying the validity of published work is core to the integrity of the scholarly record, the Publisher and Editor requested to retract the article and the authors agree with this. We have been informed in our decision-making by our editorial policies and COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Sonodynamic therapy (SDT) is an emerging noninvasive treatment modality that utilizes low-frequency and low-intensity ultrasound (US) to trigger sensitizers to kill tumor cells with reactive oxygen species (ROS). Although SDT has attracted much attention for its properties including high tumor specificity and deep tissue penetration, its anticancer efficacy is still far from satisfactory. As a result, new strategies such as gas-assisted therapy have been proposed to further promote the effectiveness of SDT. In this review, the mechanisms of SDT and gas-assisted SDT are first summarized. Then, the applications of gas-assisted SDT for cancer therapy are introduced and categorized by gas types. Next, therapeutic systems for SDT that can realize real-time imaging are further presented. Finally, the challenges and perspectives of gas-assisted SDT for future clinical applications are discussed.

Kun Qiao,1,* Cheng Luo,2,* Rong Huang,3,4 Jingfeng Xiang,5 You Pan,3,4 Shiyuan Zhang,1 Cong Jiang,1 Shuaijie Ding,6 Huawei Yang,3,4 Yuanxi Huang,1 Shipeng Ning3,4 1Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, People’s Republic of China; 2Department of Anesthesiology, The Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530000, People’s Republic of China; 3Guangxi Medical University Cancer Hospital, Nanning, 530000, People’s Republic of China; 4Key Laboratory of Breast Cancer Diagnosis and Treatment Research of Guangxi Department of Education, Nanning, 530000, People’s Republic of China; 5Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China; 6Department of Gastrointestinal Surgery & Department of Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, 518020, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shipeng Ning; Yuanxi Huang, Email nspdoctor@163.com; rxwk@163.comIntroduction: Sonodynamic therapy (SDT) as an emerging tumor treatment gained wide attention. However, tumor vascular destruction and oxygen depletion in SDT process may lead to further hypoxia. This may lead to enhanced glycolysis, lactate accumulation, and immunosuppression.Methods: A glycolysis inhibitor (3PO) loaded and PEG modified black phosphorus nanosheets (BO) is constructed for potent starvation therapy and efficient immune activation.Results: Under ultrasound irradiation, the BO can produce ROS to destroy tumors and tumor blood vessels and lead to further hypoxia and nutrients block. Then, the released 3PO inhibits tumor glycolysis and prevents the hypoxia-induced glycolysis and lactate accumulation. Both SDT and 3PO can cut off the source of lactic acid, as well as achieve antitumor starvation therapy through the blockade of the adenosine triphosphate (ATP) supply. In addition, the combination of starvation treatment and SDT further facilitates dendritic cells (DC) maturation, promotes antigen presentation by DCs, and eventually propagates the antitumor immunity and inhibition of abscopal tumor growth.Conclusion: This is the first time that combines SDT with inhibition of glycolysis, achieving admirable tumor treatment and decreasing adverse events caused by SDT process and that has caused good immune activation. Our system provides a new idea for the future design of anti-tumor nanomedicines.Keywords: sonodynamic therapy, glycolysis inhibitor, black phosphorus nanosheets, starvation therapy, immune activation

Ovarian cancer presents a substantial challenge due to its high mortality and recurrence rates among gynecological tumors. Existing clinical chemotherapy treatments are notably limited by drug resistance and systemic toxic side effects caused by off target drugs. Sonodynamic therapy (SDT) has emerged as a promising approach in cancer treatment, motivating researchers to explore synergistic combinations with other therapies for enhanced efficacy. In this study, we developed magnetic sonodynamic nanorobot (Fe3O4@SiO2-Ce6, FSC) by applying a SiO2 coating onto Fe3O4 nanoparticle, followed by coupling with the sonosensitizer Ce6. The magnetic FSC nanorobot collectives could gather at fixed point and actively move to target site regulated by magnetic field. In vitro experiments revealed that the magnetic FSC nanorobot collectives enabled directional navigation to the tumor cell area under guidance. Furthermore, under low-intensity ultrasonic stimulation, FSC nanorobot collectives mediated sonodynamic therapy exhibited remarkable anti-tumor performance. These findings suggest that magnetically actuated sonodynamic nanorobot collectives hold promising potential for application in target cancer therapy.

Articular cartilage regeneration is still a difficult task due to the cartilage’s weak capacity for self-healing and the effectiveness of the available therapies. The engineering of cartilage tissue has seen widespread use of stem cell-based therapies. However, efficient orientation of line-specific bone marrow mesenchymal stem cells (BMSCs) to chondrogenesis and maintenance of chondrogenic differentiation challenged stem cell-based therapy. Herein, we developed a Fe-based metal-organic framework (MOF) loaded with hematoporphyrin monomethyl ether (HMME) and cartilage-targeting arginine-aspartate-glycine (RGD) peptide to form MOF-HMME-RGD sonosensitizer to regulate BMSCs chondrogenic differentiation for cartilage regeneration via the modulation of reactive oxygen species (ROS). By using sonodynamic therapy (SDT), the MOF-HMME-RGD demonstrated favorable biocompatibility, could generate a modest amount of ROS, and enhanced BMSCs chondrogenic differentiation through increased accumulation of glycosaminoglycan, an ECM component specific to cartilage, and upregulated expression of key chondrogenic genes (ACAN, SOX9, and Col2a1). Further, transplanted BMSCs loading MOF-HMME-RGD combined with SDT enhanced cartilage regeneration for cartilage defect repair after 8 weeks into treatment. This synergistic strategy based on MOF nanoparticles provides an instructive approach to developing alternative sonosensitizers for cartilage regeneration combined with SDT.

Abstract Albeit nanozymes‐based tumor catalytic therapy (NCT) relies on endogenous chemical reactions that could achieve tumor microenvironment (TME)‐specialized reactive oxygen species (ROS) production, the unsatisfactory catalytic activity of nanozymes accompanied by complex TME poses a barrier to the therapeutic effect of NCT. Herein, a one‐step in situ synthesis strategy is reported to construct ternary Ru/TiO2−x@TiCN heterojunctions through oxidative conversion of TiCN nanosheets (NSs) to TiO2−x NSs and reductive deposition of Ru3+ to Ru nanoparticles. The narrow bandgap and existence of heterojunctions enhance the ultrasound‐activated ROS generation of Ru/TiO2−x@TiCN because of the accelerated electron transfer and inhibits electron–hole pair recombination. The augmented ROS production efficiency is achieved by Ru/TiO2−x@TiCN with triple enzyme‐like activities, which amplifies the ROS levels in a cascade manner through the catalytic decomposition of endogenous H2O2 to relieve hypoxia and heterojunction‐mediated NCT, as well as depletion of overexpressed glutathione. The satisfactory therapeutic effects of Ru/TiO2−x@TiCN heterojunctions are achieved through synergetic sonodynamic therapy and NCT, which achieve the complete elimination of tumors without recurrence. This strategy highlights the potential of in situ synthesis of semiconductor heterojunctions as enhanced sonosensitizers and nanozymes for efficient tumor therapy.

Abstract Due to the specific advantages of ultrasound (US) in therapeutic disease treatments, the unique therapeutic US technology has emerged. In addition to featuring a low‐invasive targeted cancer‐cell killing effect, the therapeutic US technology has been demonstrated to modulate the tumor immune landscape, amplify the therapeutic effect of other antitumor therapies, and induce immunosensitization of tumors to immunotherapy, shedding new light on the cancer treatment. Tremendous advances in nanotechnology are also expected to bring unprecedented benefits to enhancing the antitumor efficiency and immunological effects of therapeutic US, as well as therapeutic US‐derived bimodal and multimodal synergistic therapies. This comprehensive review summarizes the immunological effects induced by different therapeutic US technologies, including ultrasound‐mediated micro‐/nanobubble destruction (UTMD/UTND), sonodynamic therapy (SDT), and focused ultrasound (FUS), as well as the main underlying mechanisms involved. It is also discussed that the recent research progress of engineering intelligent nanoplatform in improving the antitumor efficiency of therapeutic US technologies. Finally, focusing on clinical translation, the key issues and challenges currently faced are summarized, and the prospects for promoting the clinical translation of these emerging nanomaterials and ultrasonic immunotherapy in the future are proposed.

Due to the complicated tumor microenvironment that compromises the efficacies of various therapies, the effective treatment of pancreatic cancer remains a big challenge. Sono‐activatable semiconducting polymer nanoreshapers (SPNDNH) are constructed to multiply remodel tumor microenvironment of orthotopic pancreatic cancer for potent immunotherapy. SPNDNH contain a semiconducting polymer, hydrogen sulfide (H2S) donor, and indoleamine 2,3‐dioxygenase (IDO) inhibitor (NLG919), which are encapsulated by singlet oxygen (1O2)‐responsive shells with modification of hyaluronidase (HAase). After accumulation in orthotopic pancreatic tumor sites, SPNDNH degrade the major content of tumor microenvironment hyaluronic acid to promote nanoparticle enrichment and immune cell infiltration, and also release H2S to relieve tumor hypoxia via inhibiting mitochondrion functions. Moreover, the relieved hypoxia enables amplified sonodynamic therapy (SDT) under ultrasound (US) irradiation with generation of 1O2, which leads to immunogenic cell death (ICD) and destruction of 1O2‐responsive components to realize sono‐activatable NLG919 release for reversing IDO‐based immunosuppression. Through such a multiple remodeling mechanism, a potent antitumor immunological effect is triggered after SPNDNH‐based treatment. Therefore, the growths of orthotopic pancreatic tumors in mouse models are almost inhibited and tumor metastases are effectively restricted. This study offers a sono‐activatable nanoplatform to multiply remodel tumor microenvironment for effective and precise immunotherapy of deep‐tissue orthotopic tumors. [ABSTRACT FROM AUTHOR]

Gliomas are one of the most common primary malignant tumours of the central nervous system (CNS), of which glioblastomas (GBMs) are the most common and destructive type. The glioma tumour microenvironment (TME) has unique characteristics, such as hypoxia, the blood-brain barrier (BBB), reactive oxygen species (ROS) and tumour neovascularization. Therefore, the traditional treatment effect is limited. As cellular oxidative metabolites, ROS not only promote the occurrence and development of gliomas but also affect immune cells in the immune microenvironment. In contrast, either too high or too low ROS levels are detrimental to the survival of glioma cells, which indicates the threshold of ROS. Therefore, an in-depth understanding of the mechanisms of ROS production and scavenging, the threshold of ROS, and the role of ROS in the glioma TME can provide new methods and strategies for glioma treatment. Current methods to increase ROS include photodynamic therapy (PDT), sonodynamic therapy (SDT), and chemodynamic therapy (CDT), etc., and methods to eliminate ROS include the ingestion of antioxidants. Increasing/scavenging ROS is potentially applicable treatment, and further studies will help to provide more effective strategies for glioma treatment. [ABSTRACT FROM AUTHOR]

Sonodynamic therapy (SDT) has aroused great interest for its potential in the treatment of glioblastoma (GBM). SDT relies on tumor-selective accumulation of a sonosensitizer that is activated by ultrasound irradiation (UI) to generate cytotoxic actions. The efficacy of GBM-SDT depends on sufficient sonosensitizer buildup in the tumor, which is, however, seriously hampered by the anatomical and biochemical barriers of the GBM. To overcome this difficulty, we herein propose a delivery strategy of 'platelets with ultrasound-triggered release property', which takes advantage of 1) the platelets' ability to carry cargo and release cargo upon activation, and 2) the ROS-generating property of SDT. To provide proof of concept for the strategy, we first stably loaded platelets with IOPD-Ce6, a nano-formed sonosensitizer consisting of iron oxide nanoparticles coated with polyglycerol and doxorubicin and loaded with chlorine e6. UI of the IOPD-Ce6-loaded platelets (IOPD-Ce6@Plt) elicited ROS generation in the IOPD-Ce6@Plt, which were immediately activated to release IOPD-Ce6 into GBM cells in co-culture which, when subjected to a second time of UI, exhibited pronounced ROS production, DNA injury, viability loss, and cell death in the GBM cells. In the in vivo experiments, mice bearing intracranial GBM grafts exhibited substantial tumor distribution of IOPD-Ce6 following intravenous injection of IOPD-Ce6@Plt and subsequent UI at the tumor site. The GBM grafts then exhibited pronounced cell injury and death after another round of UI of the tumors. Finally, the growth of intra-cranial GBM grafts was significantly slowed when an SDT protocol consisting of an intravenous IOPD-Ce6@Plt injection followed by multiple times of tumor UI had been applied twice to the mice. Our results are strong evidence for the idea that platelets are sound and amenable carriers to deliver sonosensitizers in the GBM in an ultrasound-triggered manner and thus to produce highly targeted and effective SDT of GBM. [ABSTRACT FROM AUTHOR]

Superlattices have considerable potential as sonosensitizers for cancer therapy because of their flexible and tunable band gaps, although they have not yet been reported. In this study, a Ti‐based organic–inorganic superlattice with good electron–hole separation was synthesized, which consisted of orderly layered superlattices of 2,2′‐bipyridine‐5,5′‐dicarboxylic acid (BPDC) and Ti−O layers. In addition, the superlattice was coordinated with Fe(III) and encapsulated doxorubicin (DOX) to prepare Ti‐BPDC@Fe@DOX@PEG (TFDP) after biocompatibility modification. TFDP can realize the simultaneous generation of reactive oxygen species and release of DOX under ultrasound irradiation. Moreover, adjusting the Fe(III) content can effectively modulate the band gap of the superlattice and increase the efficiency of sonodynamic therapy (SDT). The mechanisms underlying this modulation were explored. TFDP with Fe(III) can also be used as a contrast agent for magnetic resonance imaging (MRI). Both in vitro and in vivo experiments demonstrated the ability of TFDP to precisely treat cancer using MRI‐guided SDT/chemotherapy. This study expands the applications of superlattices as sonosensitizers with flexible and tailored modifications and indicates that superlattices are promising for precise and customized treatments. [ABSTRACT FROM AUTHOR]

[Display omitted] Sonodynamic therapy (SDT) can generate reactive oxygen species to kill cancer cells by activating sonosensitizers under ultrasound (US) irradiation. Nevertheless, its application is greatly limited by low quantum yield of sonosensitizers, high levels of endogenous glutathione (GSH) and tumor hypoxia. Herein, a GSH-activated sonosensitizers with synergistic therapy effect (chemodynamic therapy (CDT) and SDT) are developed by depositing Fe(III)-artemisinin infinite coordination polymers (Fe(III)-ART CPs) in pores of mesoporous TiO 2 nanoparticles (NPs). The formed Fe(III)-ART-TiO 2 NPs have high sono-induced electron-hole separation efficiency because the deposited Fe(III)-ART CPs can provide isolated intermediate bands to capture sono-induced electrons in TiO 2 NPs. Meanwhile, Fe3+ in Fe(III)-ART-TiO 2 NPs are reduced to Fe2+ by GSH with oxygen-deficient sites generated to further capture sono-induced electrons in TiO 2 NPs. Based on this, the reaction efficiency between water molecules and sono-induced holes is high enough to generate numerous hydroxyl radicals (•OH) without oxygen participated for overcoming tumor hypoxia. Additionally, through consuming GSH, the generated Fe2+ can catalyze ART to produce C-centered free radicals for CDT. Owing to these characteristics, Fe(III)-ART-TiO 2 NPs show significant tumor suppression ability and good biocompatibility in vivo. The strategy of using CDT agent to modify sonosensitizers offers new options to improve SDT effect without introducing harmful substances. [ABSTRACT FROM AUTHOR]

Sonodynamic therapy (SDT) utilizes ultrasound‐irradiating sonosensitizers to convert ultrasonic vibrations into chemical energy and produce reactive oxygen species (ROS) that cause cell apoptosis or necrosis. SDT demonstrates significant potential in the treatment of deep tumors without normal tissue damage. Rapid advances in the efficacy of SDT have enabled the rational design and construction of novel intelligent sonocatalytic nanoagents (SCNs) with various functions for versatile biomedical applications. Herein, the most recent critical advancements in intelligent SCNs for energy conversion‐based therapies are discussed. Typical SCNs including organic molecules, organic micro‐/nanoparticles, inorganic micro‐/nanoparticles, organic/inorganic hybrids, and piezoelectric materials are introduced and summarized in detail. Furthermore, these intelligent SCNs are designed for different energy conversion‐based therapies such as SDT, SDT‐assisted chemotherapy, SDT‐assisted photodynamic therapy, SDT‐assisted photothermal therapy, SDT‐assisted gas therapy, SDT‐assisted sonoporation from the cell membrane to the blood brain barrier, and high‐intensity focused ultrasound‐based sonothermal therapy. It is believed that this review will provide an overview of the application of intelligent SCNs in sonodynamic therapies to better understand the limitations and challenges of these SCNs and further promote their advancements for a broad range of biomedical applications. [ABSTRACT FROM AUTHOR]

Microbubbles loaded with Rose Bengal and docetaxel (DTX-MB-RB) were more effective when activated using ultrasound than a standard dose of docetaxel. [Display omitted] Docetaxel (DTX) chemotherapy is commonly used in the treatment of patients with advanced prostate cancer demonstrating modest improvements in survival. As these patients are often elderly and the chemotherapy treatment is not targeted, it is often poorly tolerated. More targeted approaches that increase therapeutic efficacy yet reduce the amount of toxic chemotherapy administered are needed. In this manuscript, we investigate the potential of ultrasound targeted microbubble destruction (UTMD) to deliver a combination of docetaxel chemotherapy and Rose Bengal mediated sonodynamic therapy (SDT) in pre-clinical prostate cancer models. A Rose Bengal modified phospholipid was synthesized and used as a component lipid to prepare a microbubble (MB) formulation that was also loaded with DTX. The DTX-MB-RB formulation was used in the UTMD mediated treatment of androgen sensitive and androgen resistant 3D spheroid and murine models of prostate cancer. Results from the 3D spheroid experiments showed UTMD mediated DTX-MB-RB chemo-sonodynamic therapy to be significantly more effective at reducing cell viability than UTMD mediated DTX or SDT treatment alone. In an androgen sensitive murine model of prostate cancer, UTMD mediated DTX-MB-RB chemo-sonodynamic therapy was as effective as androgen deprivation therapy (ADT) at controlling tumour growth. However, when both treatments were combined, a significant improvement in tumour growth delay was observed. In an androgen resistant murine model, UTMD mediated DTX-MB-RB chemo-sonodynamic therapy was significantly more effective than standard DTX monotherapy. Indeed, the DTX dose administered using the DTX-MB-RB formulation was 91% less than standard DTX monotherapy. As a result, UTMD mediated DTX-MB-RB treatment was well tolerated while animals treated with DTX monotherapy displayed significant weight loss which was attributed to acute toxic effects. These results highlight the potential of UTMD mediated DTX-MB-RB chemo-sonodynamic therapy as a targeted, well tolerated alternative treatment for advanced prostate cancer. [ABSTRACT FROM AUTHOR]

Cancer sonodynamic therapy (SDT) is the therapeutic strategy of a high-frequency ultrasound (US) combined with a special sonosensitizer that becomes cytotoxic upon US exposure. The growing number of newly discovered sonosensitizers and custom US in vitro treatment solutions push the SDT field into a need for systemic studies and reproducible in vitro experimental set-ups. In the current research, we aimed to compare two of the most used and suitable SDT in vitro set-ups—"sealed well" and "transducer in well"—in one systematic study. We assessed US pressure, intensity, and temperature distribution in wells under US irradiation. Treatment efficacy was evaluated for both set-ups towards cancer cell lines of different origins, treated with two promising sonosensitizer candidates—carbon nanoparticle C60 fullerene (C60) and herbal alkaloid berberine. C60 was found to exhibit higher sonotoxicity toward cancer cells than berberine. The higher efficacy of sonodynamic treatment with a "transducer in well" set-up than a "sealed well" set-up underlined its promising application for SDT in vitro studies. The "transducer in well" set-up is recommended for in vitro US treatment investigations based on its US-field homogeneity and pronounced cellular effects. Moreover, SDT with C60 and berberine could be exploited as a promising combinative approach for cancer treatment. [ABSTRACT FROM AUTHOR]

Sonodynamic therapy (SDT) is a physical therapy that utilizes critical sonosensitizers triggered by ultrasound to achieve an effective non-invasive tumor treatment. However, the inadequate sonodynamic efficacy and low responsive activities of traditional inorganic sonosensitizers have hindered its practical application. Here, we rationally design a platinum–zinc oxide (Pt ZnO) sonosensitizer to significantly enhance the efficacy of SDT through its inherent bandgap structure and dual-nanozyme activities. The Pt ZnO possesses a narrow bandgap (2.89 eV) and an appropriate amount of oxygen defects, which promote the efficiency of electrons and holes separation and the generation of reactive oxygen species (ROS) under US irradiation. Simultaneously, the Pt ZnO exhibits both catalase-like and peroxidase-like activities, which effectively catalyze endogenous H 2 O 2 into a large number of O 2 and toxic hydroxyl radicals (•OH), thus achieving an efficient enhancement of SDT and catalytic therapy. Moreover, the Pt ZnO has significant glutathione consumption performance, further amplifying the oxidative stress. Ultimately, the Pt ZnO achieves a triple ROS amplification effect, with the yields of singlet oxygen (1O 2) and •OH reaching 859.1 % and 614.4 %, respectively, inducing a highly effective sono-catalytic therapy with a remarkable tumor inhibition rate of 98.1 %. This study expands the application of ZnO semiconductor heterojunctions in the nanomedicine area, and the simple yet efficient design of the Pt ZnO provides a strategy for the development of sonosensitizers. A platinum-zinc oxide (Pt ZnO) heterojunction sonosensitizer is constructed with dual-nanozyme activities and achieves a triple ROS amplification effect, leading to an efficient synergistic sono-catalytic therapy. The Pt ZnO owns an inherent narrow bandgap and abundant oxygen defects, thus exhibiting an efficient sonosensitizer performance. It also possesses both catalase-like and peroxidase-like activities, which effectively catalyze the endogenous H 2 O 2 into a large quantity of O 2 and toxic hydroxyl radicals, thereby enhancing the SDT and catalytic therapy. Furthermore, its prominent glutathione consumption performance further amplifies oxidative stress. The yields of singlet oxygen and hydroxyl radicals reach up to 859.1 % and 614.4 %, respectively, inducing a highly effective sono-catalytic therapy with an impressive tumor inhibition rate of 98.1 %. [Display omitted] [ABSTRACT FROM AUTHOR]

The decomposition of an organic compound by irradiation with visible light and ultrasound was successfully improved by laser irradiation to TiO2 particles. Micron-size TiO2 powders as raw material in water were irradiated with a laser beam (Nd:YAG, SHG) to obtain nanoparticles. Nanoparticles were examined by scanning electron microscopy (SEM), dynamic light scattering (DLS), X-ray diffraction (XRD), and spectrophotometry. The primary particle size was reduced at high laser fluence. The secondary particle size was reduced to approximately 107 nm from micron size by laser irradiation. The irradiation of laser to anatase TiO2 did not change the crystal structure. Although laser irradiation to TiO2 reduced the photocatalytic properties for UV light, it realized photocatalytic properties for visible light. Laser irradiation to TiO2 the bandgap. Laser irradiation to TiO2 enhanced ultrasound-induced decomposition of an organic compound. [ABSTRACT FROM AUTHOR]

The lethality and chemotherapy resistance of pancreatic cancer necessitates the urgent development of innovative strategies to improve patient outcomes. To address this issue, we designed a novel drug delivery system named GDMCN2,which uses iron‐based metal organic framework (Fe‐MOF) nanocages encased in a covalent organic framework (COF) and modified with the pancreatic cancer‐specific antibody, NRP2. After being targeted into tumor cells, GDMCN2 gradually release the sonosensitizer sinoporphyrin sodium (DVDMS) and chemotherapeutic gemcitabine (GEM) and simultaneously generated reactive oxygen species (ROS) under ultrasound (US) irradiation. This system can overcome gemcitabine resistance in pancreatic cancer and reduce its toxicity to non‐targeted cells and tissues. In a mechanistic cascade, the release of ROS activates the mitochondrial transition pore (MPTP), leading to the release of Ca2+ and induction of endoplasmic reticulum (ER) stress. Therefore, microtubule‐associated protein 1A/1B‐light chain 3 (LC3) is activated, promoting lysosomal autophagy. This process also induces autophagy‐dependent ferroptosis, aided by the upregulation of Nuclear Receptor Coactivator 4 (NCOA4). This mechanism increases the sensitivity of pancreatic cancer cells to chemotherapeutic drugs and increases mitochondrial and DNA damage. The findings demonstrate the potential of GDMCN2 nanocages as a new avenue for the development of cancer therapeutics. [ABSTRACT FROM AUTHOR]

Cytokine therapy mediates the interaction between immune cells and non‐immune cells in the tumor microenvironment (TME), forming a promising approach in cancer therapy. However, the dose‐dependent adverse effects and non‐selective stimulation of cytokines limit their clinical use. We herein report a sonodynamic cytokine nano‐immunocomplex (SPNAI) that specifically activates effector T cells (Teffs) for antitumor immunotherapy. By conjugating anti‐interleukin‐2 (anti‐IL‐2) antibodies S4B6 on the semiconducting polymer nanoparticles to afford SPNA, this nanoantibody SPNA can bind with IL‐2 to form SPNAI which can block the interaction between IL‐2 and regulatory T cells (Tregs), selectively activating Teffs in TME. Moreover, SPNAI generates 1O2 to trigger immunogenic cell death of cancer cells upon sono‐irradiation, which promotes the maturation of dendritic cells and the proliferation of Teffs. This SPNAI‐mediated combination sonodynamic immunotherapy thus elevates the ratio of Teffs/Tregs in TME, resulting in inhibition of tumor growth, suppression of lung metastasis and prevention of tumor relapse. [ABSTRACT FROM AUTHOR]

Sonodynamic therapy (SDT) has emerged as an encouraging noninvasive technique that uses ultrasound to activate targeted agents to induce antitumor effects for the treatment of glioma. With extensive variation in the types of sonosensitizers, protocols for sonication, and model systems, a comprehensive overview of existing preclinical data on the efficacy of SDT in glioma treatment is warranted. Here, we conduct a systematic review of preclinical and early clinical literature on implementing SDT to treat in vitro and in vivo models of glioma. Our findings suggest that coupling sonosensitizers such as 5-aminolevulinic acid, hematoporphyrin monomethyl ether, and sinoporphyrin sodium with focused ultrasound induces robust cytotoxic activity in tumor cells (in vitro and in vivo). These effects are likely mediated by the oxidative stress induced by reactive oxygen species production, apoptotic signaling cascades, and intracellular calcium overload. Future research is needed to better understand the biochemical and mechanistic properties of SDT, and ongoing trials may help elucidate the clinical feasibility of glioma treatment with optimized sonically activated treatments. [ABSTRACT FROM AUTHOR]

Abstract Prolonged and incurable bacterial infections in soft tissue and bone are currently causing large challenges in the clinic. Two-dimensional (2D) materials have been designed to address these issues, but materials with satisfying therapeutic effects are still needed. Herein, CaO2-loaded 2D titanium carbide nanosheets (CaO2-TiOx@Ti3C2, C-T@Ti3C2) were developed. Surprisingly, this nanosheet exhibited sonodynamic ability, in which CaO2 caused the in situ oxidation of Ti3C2 MXene to produce acoustic sensitiser TiO2 on its surface. In addition, this nanosheet displayed chemodynamic features, which promoted a Fenton reaction triggered by self-supplied H2O2. We detected that C-T@Ti3C2 nanosheets increased reactive oxygen species (ROS) production in response to sonodynamic therapy, which displayed an ideal antibacterial effect. Furthermore, these nanoreactors facilitated the deposition of Ca2+, which promoted osteogenic transformation and enhanced bone quality in osteomyelitis models. Herein, a wound healing model and prosthetic joint infection (PJI) model were established, and the C-T@Ti3C2 nanosheets played a protective role in these models. Taken together, the results indicated that the C-T@Ti3C2 nanosheets function as a multifunctional instrument with sonodynamic features, which might reveal information regarding the treatment of bacterial infections during wound healing. Graphical Abstract

Jing Wang,1,* Weijian Chen,1,2,* Wenxiang Du,2 Hongjie Zhang,2 Matthias Ilmer,3 Lei Song,2 Yuan Hu,2 Xiaopeng Ma1 1Department of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, People’s Republic of China; 2State Key Laboratory of Fire Science, University of Science and Technology of China, Hefei, Anhui, 230026, People’s Republic of China; 3Department of General, Visceral, and Transplantation Surgery, Ludwig-Maximilians-University (LMU), Campus Grosshadern, Munich, 81377, Germany*These authors contributed equally to this workCorrespondence: Yuan Hu; Xiaopeng Ma, Email yuanhu@ustc.edu.cn; XiaopengMa@fsyy.ustc.edu.cnIntroduction: Tamoxifen (TAM) has proven to be a therapeutic breakthrough to reduce mortality and recurrence in estrogen receptor-positive (ER+) breast cancer patients. However, the application of TAM exhibits low bioavailability, off-target toxicity, instinct and acquired TAM resistance.Methods: We utilized black phosphorus (BP) as a drug carrier and sonosensitizer, integrated with TAM and tumor-targeting ligand folic acid (FA) to construct TAM@BP-FA for synergistic endocrine and sonodynamic therapy (SDT) of breast cancer. The exfoliated BP nanosheets were modified through in situ polymerization of dopamine, followed by electrostatic adsorption of TAM and FA. The anticancer effect of TAM@BP-FA was evaluated through in vitro cytotoxicity and in vivo antitumor model. RNA-sequencing (RNA-seq), quantitative real-time PCR, Western blot analysis, flow cytometry analysis and peripheral blood mononuclear cells (PBMCs) analysis were performed for mechanism investigation.Results: TAM@BP-FA had satisfactory drug loading capacity, the TAM release behavior can be controlled through pH microenvironment and ultrasonic stimulation. An amount of hydroxyl radical (∙OH) and singlet oxygen (1O2) were as expected generated under ultrasound stimulation. TAM@BP-FA nanoplatform showed excellent internalization in both TAM-sensitive MCF7 and TAM-resistant (TMR) cells. Using TMR cells, TAM@BP-FA displayed significantly enhanced antitumor ability in comparison with TAM (7.7% vs 69.6% viability at 5μg/mL), the additional SDT further caused 15% more cell death. RNA-seq unraveled the TAM@BP-FA antitumor mechanisms including effects on cell cycle, apoptosis and cell proliferation. Further analysis showed additional SDT successfully triggering reactive oxygen species (ROS) generation and mitochondrial membrane potential (MMP) reduction. Moreover, PBMCs exposed to TAM@BP-FA induced an antitumor immune response by natural killer (NK) cell upregulation and immunosuppression macrophage reduction.Conclusion: The novel BP-based strategy not only delivers TAM specifically to tumor cells but also exhibits satisfactory antitumor effects through targeted therapy, SDT, and immune cell modulation. The nanoplatform may provide a superior synergistic strategy for breast cancer therapy.Keywords: black phosphorus, breast cancer, sonodynamic therapy, tamoxifen, PBMC, combination therapy

Shihui Guan, Dengke Teng, Hui Wang,* Qimeihui Wang,* Xi Zhen, Guoqing Sui, Yang Wang, Lingyu Zhu, Yuanqiang Lin, Dan Jiao, Feng Guo Department of Ultrasound, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, 130033, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hui Wang; Qimeihui Wang, Email whui66@jlu.edu.cn; wangqmh@jlu.edu.cnIntroduction: In order to diagnose and treat papillary thyroid carcinoma (PTC) accurately, phase-transition nanoparticles, P@IP-miRNA (PFP@IR780/PLGA-bPEI-miRNA338-3p), was engineered. The nanoparticles (NPs) can target the tumor cells, realize the multimodal imaging, and provide sonodynamic-gene therapy for PTC.Methods: P@IP-miRNA NPs were synthesized through double emulsification method, and miRNA338-3p was attached to the surface of the NPs by electrostatic adsorption. The characterization of NPs was detected to screen out qualified nanoparticles. In vitro, laser confocal microscopy and flow cytometry were used to detect the targeting and subcellular localization of NPs. Western blot, qRT-PCR, and immunofluorescence were used to detect the ability to transfect miRNA. CCK8 kit, laser confocal microscopy and flow cytometry were used to detect the inhibition on TPC-1 cells. In vivo experiments were performed based on tumor-bearing nude mice. The efficacy of combined treatment by NPs was comprehensively evaluated, and the multimodal imaging ability of NPs in vivo and in vitro was detected.Results: P@IP-miRNA NPs were successfully synthesized which have spherical shape, uniform size, good dispersion and positive potential. The encapsulation rate of IR780 was (82.58± 3.92) %, the drug loading rate was (6.60± 0.32) %, and the adsorption capacity of miRNA338-3p was 41.78 μg/mg. NPs have excellent tumor targeting ability, miRNA transfection ability, ROS production ability and multimodal imaging ability in vivo and in vitro. The antitumor effect of combined treatment group was the best, and the efficacy was better than that of single factor treatment group, and the difference was statistically significant.Conclusion: P@IP-miRNA NPs can realize multimodal imaging and sonodynamic-gene therapy, providing a new idea for accurate diagnosis and treatment of PTC.Keywords: papillary thyroid carcinoma, miRNA338-3P, sonodynamic therapy, nanoparticles, multimodal imaging

Sonodynamic therapy (SDT) has attracted significant attention in recent years as it is an innovative approach to tumor treatment. It involves the utilization of sound waves or ultrasound (US) to activate acoustic sensitizers, enabling targeted drug release for precise tumor treatment. This review aims to provide a comprehensive overview of SDT, encompassing its underlying principles and therapeutic mechanisms, the applications of nanomaterials, and potential synergies with combination therapies. The review begins by introducing the fundamental principle of SDT and delving into the intricate mechanisms through which it facilitates tumor treatment. A detailed analysis is presented, outlining how SDT effectively destroys tumor cells by modulating drug release mechanisms. Subsequently, this review explores the diverse range of nanomaterials utilized in SDT applications and highlights their specific contributions to enhancing treatment outcomes. Furthermore, the potential to combine SDT with other therapeutic modalities such as photothermal therapy (PTT) and chemotherapy is discussed. These combined approaches aim to synergistically improve therapeutic efficacy while mitigating side effects. In conclusion, SDT emerges as a promising frontier in tumor treatment that offers personalized and effective treatment options with the potential to revolutionize patient care. As research progresses, SDT is poised to play a pivotal role in shaping the future landscape of oncology by providing patients with a broader spectrum of efficacious and tailored treatment options.

Abstract Due to the complicated tumor microenvironment that compromises the efficacies of various therapies, the effective treatment of pancreatic cancer remains a big challenge. Sono‐activatable semiconducting polymer nanoreshapers (SPNDNH) are constructed to multiply remodel tumor microenvironment of orthotopic pancreatic cancer for potent immunotherapy. SPNDNH contain a semiconducting polymer, hydrogen sulfide (H2S) donor, and indoleamine 2,3‐dioxygenase (IDO) inhibitor (NLG919), which are encapsulated by singlet oxygen (1O2)‐responsive shells with modification of hyaluronidase (HAase). After accumulation in orthotopic pancreatic tumor sites, SPNDNH degrade the major content of tumor microenvironment hyaluronic acid to promote nanoparticle enrichment and immune cell infiltration, and also release H2S to relieve tumor hypoxia via inhibiting mitochondrion functions. Moreover, the relieved hypoxia enables amplified sonodynamic therapy (SDT) under ultrasound (US) irradiation with generation of 1O2, which leads to immunogenic cell death (ICD) and destruction of 1O2‐responsive components to realize sono‐activatable NLG919 release for reversing IDO‐based immunosuppression. Through such a multiple remodeling mechanism, a potent antitumor immunological effect is triggered after SPNDNH‐based treatment. Therefore, the growths of orthotopic pancreatic tumors in mouse models are almost inhibited and tumor metastases are effectively restricted. This study offers a sono‐activatable nanoplatform to multiply remodel tumor microenvironment for effective and precise immunotherapy of deep‐tissue orthotopic tumors.

Burgeoning is an evolution from conventional photodynamic therapy (PDT). Thus, sonodynamic therapy (SDT) regulated by nanoparticles (NPs) possesses multiple advantages, including stronger penetration ability, better biological safety, and not reactive oxygen species (ROS)-dependent tumor-killing effect. However, the limitation to tumor inhibition instead of shrinkage and the incapability of eliminating metastatic tumors hinder the clinical potential for SDT. Fortunately, immune checkpoint blockade (ICB) can revive immunological function and induce a long-term immune memory against tumor rechallenges. Hence, synergizing NPs-based SDT with ICB can provide a promising therapeutic outcome for solid tumors. Herein, we briefly reviewed the progress in NPs-based SDT and ICB therapy. We highlighted the synergistic anti-tumor mechanisms and summarized the representative preclinical trials on SDT-assisted immunotherapy. Compared to other reviews, we provided comprehensive and unique perspectives on the innovative sonosensitizers in each trial. Moreover, we also discussed the current challenges and future corresponding solutions.

Introduction: Sonodynamic therapy (SDT) has potential clinical applications for cancer therapy, and is yet restricted by complex tumor microenvironmental (TME) factors. Thus, the research problem of TME modulation as well as efficient tumor treatment still needs to be clarified. Method: In this study, a calcium carbonate (CaCO3) nanoplatform was designed for ultrasound (US) and TME response-triggered, which encapsulated Ag2S and loaded with l-Arg, and further wrapped with RBC/Platelet membrane, named as QD@Ca/ML-Arg. Results: Non-invasive US-triggered SDT by Ag2S and acidic environment-responsive drug release were achieved. In vitro experiments validated the efficacy of SDT, Ca-ion interference and nitric oxide (NO) gas therapy as combined therapy for cancer treatment. By means of RNA sequencing, the cancer therapeutic mechanism of SDT in redox-related pathways was elucidated. The immunosuppressive TME was simulated with a M2-macrophage/cancer cell co-culture system to confirm the immune activating effect of immunogenic cell death (ICD). Conclusion: Accordingly, the potential of QD@Ca/ML-Arg-was demonstrated for in vitro TME modulation, cancer therapeutic efficacy and clinical translation.

AbstractSonodynamic therapy (SDT) has aroused great interest for its potential in the treatment of glioblastoma (GBM). SDT relies on tumor-selective accumulation of a sonosensitizer that is activated by ultrasound irradiation (UI) to generate cytotoxic actions. The efficacy of GBM-SDT depends on sufficient sonosensitizer buildup in the tumor, which is, however, seriously hampered by the anatomical and biochemical barriers of the GBM. To overcome this difficulty, we herein propose a delivery strategy of ‘platelets with ultrasound-triggered release property’, which takes advantage of 1) the platelets’ ability to carry cargo and release cargo upon activation, and 2) the ROS-generating property of SDT. To provide proof of concept for the strategy, we first stably loaded platelets with IOPD-Ce6, a nano-formed sonosensitizer consisting of iron oxide nanoparticles coated with polyglycerol and doxorubicin and loaded with chlorine e6. UI of the IOPD-Ce6-loaded platelets (IOPD-Ce6@Plt) elicited ROS generation in the IOPD-Ce6@Plt, which were immediately activated to release IOPD-Ce6 into GBM cells in co-culture which, when subjected to a second time of UI, exhibited pronounced ROS production, DNA injury, viability loss, and cell death in the GBM cells. In the in vivo experiments, mice bearing intracranial GBM grafts exhibited substantial tumor distribution of IOPD-Ce6 following intravenous injection of IOPD-Ce6@Plt and subsequent UI at the tumor site. The GBM grafts then exhibited pronounced cell injury and death after another round of UI of the tumors. Finally, the growth of intra-cranial GBM grafts was significantly slowed when an SDT protocol consisting of an intravenous IOPD-Ce6@Plt injection followed by multiple times of tumor UI had been applied twice to the mice. Our results are strong evidence for the idea that platelets are sound and amenable carriers to deliver sonosensitizers in the GBM in an ultrasound-triggered manner and thus to produce highly targeted and effective SDT of GBM.

Abstract The lethality and chemotherapy resistance of pancreatic cancer necessitates the urgent development of innovative strategies to improve patient outcomes. To address this issue, we designed a novel drug delivery system named GDMCN2,which uses iron‐based metal organic framework (Fe‐MOF) nanocages encased in a covalent organic framework (COF) and modified with the pancreatic cancer‐specific antibody, NRP2. After being targeted into tumor cells, GDMCN2 gradually release the sonosensitizer sinoporphyrin sodium (DVDMS) and chemotherapeutic gemcitabine (GEM) and simultaneously generated reactive oxygen species (ROS) under ultrasound (US) irradiation. This system can overcome gemcitabine resistance in pancreatic cancer and reduce its toxicity to non‐targeted cells and tissues. In a mechanistic cascade, the release of ROS activates the mitochondrial transition pore (MPTP), leading to the release of Ca2+ and induction of endoplasmic reticulum (ER) stress. Therefore, microtubule‐associated protein 1A/1B‐light chain 3 (LC3) is activated, promoting lysosomal autophagy. This process also induces autophagy‐dependent ferroptosis, aided by the upregulation of Nuclear Receptor Coactivator 4 (NCOA4). This mechanism increases the sensitivity of pancreatic cancer cells to chemotherapeutic drugs and increases mitochondrial and DNA damage. The findings demonstrate the potential of GDMCN2 nanocages as a new avenue for the development of cancer therapeutics.

Triple-negative breast cancer (TNBC) is a high-risk cancer, and its treatment is an important focus of biomedical research. Immuno-sonodynamic therapy (iSDT), a treatment strategy based on a combination of sonodynamic therapy (SDT) and an immune checkpoint blockade, has been proposed to achieve improved antitumor effects. In this study, chlorin e6 (Ce6) and the PD-1 inhibitor BMS202 were encapsulated into a cell membrane-camouflaged nanoliposome (Bio-Lipo-CB). SDS-PAGE assay and TEM proved the successful wrapping of cell membrane in liposomes, and Bio-Lipo-CB could selectively accumulate in 4T1 cells. Compared with Bio-Lipo-CB alone, Bio-Lipo-CB-SDT showed significant cytotoxicity with abundant ROS production and increased cell apoptosis rate. Moreover, after Bio-Lipo-CB-SDT treatment, calreticulin (CRT) extraversion to the cell membrane, HMGB1 and ATP release to extracellular, indicated immunogenic cell death (ICD). Furthermore, in vivo fluorescence imaging test showed that Bio-Lipo-CB can accumulate in the tumor site after 2 h injection. The in vivo antitumor experiment further confirmed the antitumor efficiency of Bio-Lipo-CB-SDT analysis and demonstrated that Bio-Lipo-CB-SDT induced ICD. The body weight and HE staining of normal organs primarily indicated the safety of this combined strategy. Our study is a proof of concept of synergistic tumor therapeutics based on SDT and checkpoint blockade immunotherapy using a bionic nanoplatform in TNBC. [ABSTRACT FROM AUTHOR]

With the rapid development of sonodynamic therapy (SDT), sonosensitizers have evolved from traditional treatments to comprehensive diagnostics and therapies. Sonosensitizers play a crucial role in the integration of ultrasound imaging (USI), X-ray computed tomography (CT), and magnetic resonance imaging (MRI) diagnostics while also playing a therapeutic role. This review was based on recent articles on multifunctional sonosensitizers that were used in SDT for the treatment of cancer and have the potential for clinical USI, CT, and MRI applications. Next, some of the shortcomings of the clinical examination and the results of sonosensitizers in animal imaging were described. Finally, this paper attempted to inform the future development of sonosensitizers in the field of integrative diagnostics and therapeutics and to point out current problems and prospects for their application. [ABSTRACT FROM AUTHOR]

Sonodynamic therapy (SDT) has been widely reported as a noninvasive and high‐penetration therapy for cancer; however, the design of an efficient sonosensitizer remains an urgent need. To address this issue, molybdenum disulfide nanoflowers (MoS2 NF) as piezo‐sonosensitizers and introduced sulfur vacancies on the MoS2 NF (Sv‐MoS2 NF) to improve their piezoelectric property for cancer therapy are designed. Under ultrasonic mechanical stress, the Sv‐MoS2 NF resulted in piezoelectric polarization and band tilting, which enhanced the charge carrier separation and migration. This resulted in an improved catalytic reaction for reactive oxygen species (ROS) production, ultimately enhancing the SDT performance. Thanks to the high efficiency of ROS generation, the Sv‐MoS2 NF have demonstrated a good anticancer effect in vitro and in vivo. Following a systematic evaluation, Sv‐MoS2 NF also demonstrated good biocompatibility. This novel piezo‐sonosensitizer and vacancy engineering strategy provides a promising new approach for achieving efficient SDT. [ABSTRACT FROM AUTHOR]

Recent considerable technological advances in ultrasound‐based treatment modality provides a magnificent prospect for scientific communities to conquer the related diseases, which is featured with remarkable tissue penetration, non‐invasive and non‐thermal characteristics. As one of the critical elements that influences treatment outcomes, titanium (Ti)‐based sonosensitizers with distinct physicochemical properties and exceptional sonodynamic efficiency have been applied extensively in the field of nanomedical applications. To date, a myriad of methodologies has been designed to manipulate the sonodynamic performance of titanium‐involved nanomedicine and further enhance the productivity of reactive oxygen species for disease treatments. In this comprehensive review, the sonocatalytic optimization of diversified Ti‐based nanoplatforms, including defect engineering, plasmon resonance modulation, heterojunction, modulating tumor microenvironment, as well as the development of synergistic therapeutic modalities is mainly focused. The state‐of‐the‐art Ti‐based nanoplatforms ranging from preparation process to the extensive medical applications are summarized and highlighted, with the goal of elaborating on future research prospects and providing a perspective on the bench‐to‐beside translation of these sonocatalytic optimization tactics. Furthermore, to spur further technological advancements in nanomedicine, the difficulties currently faced and the direction of sonocatalytic optimization of Ti‐based therapeutic nanomedicine are proposed and outlooked. [ABSTRACT FROM AUTHOR]

A multifunctional and potent sonosensitizer based on layered double hydroxides (LDHs) with a suitable bandgap and diverse immunological effects (activation of T cells and enhancement infiltration of T cells) was designed to facilitate high-performance SDT combined with immunotherapy. [Display omitted] Sonodynamic therapy (SDT) is a potential non-invasive therapeutic to overcome the limitation of depth and to enhance immunotherapy by converting "cold" to "hot" tumors. However, the intervention effect of SDT-induced hot tumors may not be sufficient to effectively enhance the effect of immunotherapy due to the intricate tumor microenvironment (TME). Herein, a multifunctional and potent sonosensitizer based on layered double hydroxides (LDHs) with a suitable bandgap and diverse immunological effects (activation of T cells and enhancement infiltration of T cells) was designed to facilitate high-performance SDT combined with immunotherapy. Briefly, Ca2+ was introduced into MgFe-LDH to construct MgCaFe-LDH to achieve excellent SDT performance, outstanding modulated TME ability, and a tremendous prognosis effect. The better SDT efficiency was attributed to the optimized electron structure and bandgap with increasing Ca2+ introduction. The regulation of the intricate TME by improving the hypoxic microenvironment and decreasing the concentration of glutathione (GSH) with reducibility to enhance oxidation stress further boosted the SDT effect. In addition, bioactive MgCaFe-LDH exhibited an excellent immunological function, resulting from Mg2+ and Ca2+ ions synergistically activating CD8+ and CD4+ T cells and enhancing the infiltration of T cells into tumor tissues. Moreover, the combined therapy with SDT and αCTLA-4 also displayed a suppressive effect on the bilateral tumor model. Our work highlights novel bioactive LDH sonosensitizers that integrate TME regulation, SDT, and immunological effects for efficient cancer therapy. [ABSTRACT FROM AUTHOR]

Sonodynamic therapy (SDT) induces reactive oxygen species (ROS) to kill tumor cells. Heme oxygenase-1 (HO-1), as an important antioxidant enzyme, resists killing by scavenging ROS. Zinc protoporphyrin (ZnPP) not only effectively inhibits HO-1 activity, but also becomes a potential sonosensitizer. However, its poor water solubility limits its applications. Herein, we developed an improved water-soluble method. It was proved that pegylated zinc protoporphyrin-mediated SDT (PEG-ZnPP-SDT) could significantly enhance ROS production by destroying the HO-1 antioxidant system in ovarian cancer. Increased ROS could cause mitochondrial membrane potential collapse, release cytochrome c from mitochondria to the cytoplasm, and trigger the mitochondrial–caspase apoptotic pathway. In conclusion, our results demonstrated that PEG-ZnPP-SDT, as a novel sonosensitizer, could improve the antitumor effects by destroying the HO-1 antioxidant system. It provided a new therapeutic strategy for SDT to treat cancers, especially those with higher HO-1 expression. [ABSTRACT FROM AUTHOR]

The primary purpose of this work was to design and obtain a series of curcuminoid chalcone–NSAID hybrid derivatives. The ester-type hybrid compounds with ibuprofen (i), ketoprofen (ii), and naproxen (iii) were obtained in two ways, using the Claisen–Schmidt reaction and the Steglich esterification reaction. The designed molecules were successfully synthesised, and FT-IR, MS, and NMR spectroscopy confirmed their structures. Moreover, the cytotoxic effect of the sonodynamic therapy and the anti-inflammatory, antioxidant, and anticholinergic properties of some curcuminoid chalcones and curcuminoid chalcones hybrids were evaluated. The curcuminoid chalcone derivatives showed promising neuroprotective activity as sonosensitisers for sonodynamic therapy in the studied cell lines. Additionally, the stability of the ester-type hybrid compounds with promising activity was determined. The RP-HPLC method was used to observe the degradation of the tested compounds. Studies have shown that structural isomers of ester-type hybrid compounds (3ai, 3bi) are characterised by a similar susceptibility to degradation factors, i.e., they are extremely unstable in alkaline environments, very unstable in acidic environments, unstable in neutral environments, practically stable in oxidising environments, and photolabile in solutions and in the solid phase. These compounds maintain adequate stability in environment at pH 1.2 and 6.8, which may make them good candidates for developing formulations for oral administration. [ABSTRACT FROM AUTHOR]

Sonodynamic therapy (SDT) has gained significant attention in the treatment of deep tumors and multidrug-resistant (MDR) bacterial infections due to its high tissue penetration depth, high spatiotemporal selectivity, and noninvasive therapeutic method. SDT combines low-intensity ultrasound (US) and sonosensitizers to produce lethal reactive oxygen species (ROS) and external damage, which is the main mechanism behind this therapy. However, traditional organic small-molecule sonosensitizers display poor water solubility, strong phototoxicity, and insufficient targeting ability. Inorganic sonosensitizers, on the other hand, have low ROS yield and poor biocompatibility. These drawbacks have hindered SDT's clinical transformation and application. Hence, designing stimuli-responsive nano-sonosensitizers that make use of the lesion's local microenvironment characteristics and US stimulation is an excellent alternative for achieving efficient, specific, and safe treatment. In this review, we provide a comprehensive overview of the currently accepted mechanisms in SDT and discuss the application of responsive nano-sonosensitizers in the treatment of tumor and bacterial infections. Additionally, we emphasize the significance of the principle and process of response, based on the classification of response patterns. Finally, this review emphasizes the potential limitations and future perspectives of SDT that need to be addressed to promote its clinical transformation. This review presents a comprehensive examination of the application of responsive nano-sonosensitizers in the sonodynamic therapy of tumor and bacterial infections, using the local microenvironment characteristics of the lesion and US stimulation to achieve efficient, specific and safe sonodynamic therapy. The review also covers the currently accepted mechanisms of sonodynamic therapy, and identifies potential limitations and future perspectives, which are essential for promoting its clinical transformation. [Display omitted] • Sonodynamic therapy is a powerful and prospective therapeutic modality. • The mechanism of stimuli-responsive sonodynamic therapy is elucidated in detail. • Significance of the principle and process of response is emphasized. • Potential limitations and future perspectives of sonodynamic therapy is discussed. [ABSTRACT FROM AUTHOR]

Bacterial infection is the leading cause of many severe inflammation diseases. The development of novel and effective therapeutic approaches to counter bacterial infections, especially for drug-resistant bacteria, is essential. Herein, we have successfully developed an ultrasound-active tricarbonyl rhenium(I) complex with tetraphenylethylene (TPE) modification (RePy-TPE) for CO gas therapy and sonodynamic therapy of bacterial infections. RePy-TPE produced reactive oxygen species and released CO under ultrasound irradiation. In addition, RePy-TPE showed aggregation-induced emission in water due to the introduction of TPE, which enhanced the yield of 1O2 generation in a biological aqueous solution. The produced 1O2 and released CO killed mycobacterium smegmatis (M. smegmatis) and Escherichia coli (E. coli), as shown by bacterial membrane damage and biofilm elimination. Furthermore, ultrasound-active RePy-TPE perturbed the purine metabolism of the bacteria, which disturbed the biosynthesis of DNA and energy metabolism, eventually reducing the vitality of bacteria. This article provides a novel strategy for the development of ultrasound-active metal-based antibiotics. [ABSTRACT FROM AUTHOR]

An "all-in-one" phototheranostic nanoplatform based on a single NIR-II light-responsive Schottky-type Bi 2 S 3-x -Au heterostructure for photoacoustic imaging-guided sonodynamic therapy-enhanced photodynamic/photothermal therapy. [Display omitted] Bismuth sulfide is widely used as an n -type semiconductor material in photocatalytic reactions. However, bismuth sulfide has poor absorption in the near-infrared region and low charge separation efficiency, limiting its application in phototherapy and sonodynamic therapy (SDT). In this study, we successfully synthesized an "all-in-one" phototheranostic nanoplatform, namely Bi 2 S 3-x -Au@HA, based on a single second near-infrared (NIR-II) light-responsive Schottky-type Bi 2 S 3-x -Au heterostructure for photoacoustic (PA) imaging-guided SDT-enhanced photodynamic therapy (PDT)/photothermal therapy (PTT). Bi 2 S 3-x -Au@HA exhibits excellent NIR-II plasmonic and photothermal properties, rendering it with NIR-II PA imaging capabilities for accurate diagnosis. Additionally, the high-density sulfur vacancies constructed on the Bi 2 S 3 surface cause it to possess a reduced band gap (1.21 eV) that can act as an electron trap. Using the density functional theory, we confirmed that the light and ultrasound-induced electrons are more likely to aggregate on the Au nanoparticle surface through interfacial self-assembly, which promotes electron-hole separation and enhances photocatalytic activity with increased reactive oxygen species (ROS) generation. With a further modification of hyaluronic acid (HA), Bi 2 S 3-x -Au@HA can selectively target cancer cells through HA and CD44 protein interactions. Both in vitro and in vivo experiments demonstrated that Bi 2 S 3-x -Au@HA effectively suppressed tumor growth through SDT-enhanced PTT/PDT under a single NIR-II laser and ultrasound irradiation with negligible toxicity. Our findings provide a framework for fabricating Schottky-type heterostructures as single NIR-II light-responsive nanotheranostic agents for PA imaging-guided cancer phototherapy. [ABSTRACT FROM AUTHOR]

Biomimetic sonosensitizers are prepared by camouflaging polymer-based sonosensitizers with cancer cell membranes, and they achieve efficient sonodynamic ablation of deep-seated tumors. [Display omitted] • Synthesis of biomimetic sonosensitizers with cancer cell membrane camouflage. • Strong sonodynamic effects of sonosensitizers upon irradiation with ultrasound. • Long blood circulation half-life and homologous targeting ability. • Efficient ablation of deep-seated tumors due to strong sonodynamic effects. Ultrasound (US)-triggered therapies are promising in cancer treatments, and their effectiveness can be enhanced through the proper camouflage of sonosensitizers. Herein, we have constructed cancer cell membrane (CCM)-camouflaged sonosensitizers for homotypic tumor-targeted sonodynamic therapy (SDT). The camouflaged sonosensitizers have been prepared by encapsulating hemoporfin molecules in poly(lactic acid) polymers (H@PLA) and extruding with CCM from Colon Tumor 26 (CT26) cells, forming the H@PLA@CCM. Under excitation with US, the hemoporfin encapsulated in H@PLA@CCM can convert O 2 into cytotoxic 1O 2 , which exerts an efficient sonodynamic effect. The H@PLA@CCM nanoparticles show enhanced cellular internalization to CT26 cells compared to H@PLA, and they also can be more efficiently engulfed by CT26 cells than by mouse breast cancer cells, due to the homologous targeting ability of CT26 CCM. After the intravenous injection, the blood circulation half-life of H@PLA@CCM is determined to be 3.23 h which is 4.3-time that of H@PLA. With high biosafety, homogeneous targeting ability, and sonodynamic effect, the combination of H@PLA@CCM and US irradiation has induced significant apoptosis and necrosis of tumor cells through the efficient SDT, achieving the strongest inhibition rate of tumors among other groups. This study provides insights into designing efficient and targeted cancer therapies using CCM-camouflaged sonosensitizers. [ABSTRACT FROM AUTHOR]