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Sonodynamic anti-cancer therapy relies on the highly active singlet oxygen to induce potent cell death. However, the non-specific biodistribution of sonosensitizers post systemic administration results in a significant accumulation in the skin, and hence the daylight-induced phototoxicity. Here, we report a smart metal-organic framework-based nanocarrier with titanium dioxide (TiO 2) as the sonosensitizer for reduced phototoxicity in the skin. The organic ligand bears the imidazole moiety that can facilely consume singlet oxygen in the skin without compromising the anti-cancer efficacy. The reaction between imidazole moiety and singlet oxygen was confirmed by the density functional theory (DFT). Upon light irradiation, the nanocarrier can significantly reduce the phototoxicity post light irradiation in a range of normal cells in vitro and in a mouse model in vivo. Meanwhile, the ligand contains a disulfide moiety that can deplete glutathione and orchestrate the singlet oxygen-induced toxicity in the CT-26 colon cancer cells. As a result, the nanocarrier showed superior in vivo antitumor efficacy in a CT-26 tumor-bearing mice model, leading to significant suppression of tumor growth and improved animal survival rates. The current work provides a tailored nanoscale particle engineering approach to simultaneously minimize phototoxicity in the skin and sensitize sonodynamic anti-cancer therapy. [Display omitted] • The skin toxicity of sonodynamic therpay can be mitigated by tailored MOF nanocarriers. • The imidazole moiety-mediated singlet oxygen consumption is the key to skin toxicity reduction. • The thiol-disulfide exchange reaction can sensitize the sonodynamic therapy. • The imodazole moiety does not affect the anti-tumor efficacy. [ABSTRACT FROM AUTHOR]

[Display omitted] • The therapeutic effects of sonodynamic therapy based on BaTiO 3 nanoparticles was firstly evaluated by using human tumor organoids. • The dual therapy of low-intensity sonodynamic therapy and low-dose chemotherapeutic drugs could achieve a comparable therapeutic effect as high-dose drugs. • The dual therapy showed good therapeutic effects on drug-resistant tumor organoids. • This work has a potential application in evaluating patients' individual responses to the dual therapy before clinical interventions. Chemotherapy is a widely used cancer treatment, however, it can have notable side effects owing to the high-doses of drugs administered. Sonodynamic therapy (SDT) induced by sonosensitizers has emerged as a promising approach to treat cancer, however, there is limited research evaluating its therapeutic effects on human tumors. In this study, we introduced a dual therapy that combines low-dose chemotherapeutic drugs with enhanced sonodynamic therapy, utilizing barium titanate (BaTiO 3 , BTO) nanoparticles (NPs) as sonosensitizers to treat tumor organoids. We demonstrated that ultrasound could improve the cellular uptake of chemotherapy drugs, while the chemotherapeutic effect of the drugs made it easier for BTO NPs to enter tumor cells, and the dual therapy synergistically inhibited tumor cell viability. Moreover, different patient-derived tumor organoids exhibited different sensitivities to this therapy, highlighting the potential to evaluate individual responses to combination therapies prior to clinical intervention. Furthermore, this dual therapy exhibited therapeutic effects equivalent to those of high-dose chemotherapy drugs on drug-resistant tumor organoids and showed the potential to enhance the efficacy of killing drug-resistant tumors. In addition, the biosafety of the BTO NPs was successfully verified in live mice via oral administration. This evidence confirms the reliable and safe nature of the dual therapy approach, making it a feasible option for precise and personalized therapy in clinical applications. [ABSTRACT FROM AUTHOR]

Obesity plays a crucial role in the development and progression of type 2 diabetes mellitus (T2DM) by causing excessive release of free fatty acid from adipose tissue, which in turn leads to systemic infiltration of macrophages. In individuals with T2DM, the infiltration of macrophages into pancreatic islets results in islet inflammation that impairs beta cell function, as evidenced by increased apoptosis and decreased glucose‐stimulated insulin secretion. The present study aimed to investigate the effects of non‐lethal sonodynamic therapy (NL‐SDT) on bone marrow‐derived macrophages (BMDMs) exposed to high glucose and palmitic acid (HG/PA). These findings indicate that NL‐SDT facilitates the expression of DRP1 through the transient production of mitochondrial ROS, which subsequently promotes mitophagy. This mitophagy was shown to limit the activation of the NLRP3 inflammasome and the secretion of IL‐1β in BMDMs exposed to HG/PA. In co‐culture experiments, beta cells exhibited significant dysfunction when interacting with HG/PA‐treated BMDMs. However, this dysfunction was markedly alleviated when the BMDMs had undergone NL‐SDT treatment. Moreover, NL‐SDT was found to lower blood glucose levels and elevate serum insulin concentrations in db/db mice. Furthermore, NL‐SDT effectively reduced the infiltration of F4/80‐positive macrophages and the expression of CASP1 within islets. These findings provide fundamental insights into the mechanisms through which NL‐SDT may serve as a promising approach for the treatment of T2DM. [ABSTRACT FROM AUTHOR]

Ultrasound (US) becomes an appealing modality for stimulating or amplifying immune responses during cancer therapy, which is also termed sono‐immunotherapy. However, the clinical prospect has not been fully realized due to the scarcity of efficient sonosensitizers. Herein, for the first time a novel Os‐doped Au‐tri(pyridin‐4‐yl) amine coordination structure (Os@Au‐TPA)‐based sonosensitizer is originally designed and synthesized for sono‐immunotherapy of breast‐metastasized tumors. Impressively, Os@Au‐TPA shows much higher US‐mediated 1O2‐producing activity than Au‐TPA as well as the other traditional sonosensitizers, for example, ≈41.6 folds to ce6, 19.5 times to Protoporphyrin IX (PpIX), 12.0 to Indocyanine Green (ICG), and 11.1 to Iron phthalocyanine (Pc(Fe)). The Os@Au‐TPA can not only generate abundant ROS upon US irradiation to implement sonodynamic therapy (SDT), stimulating cell apoptosis and further immunogenic cell death, but can also generate O2 to alleviate hypoxia to promote the polarization of M2 to M1 macrophages to enhance tumor immunogenicity. As a result, when combined with PD‐L1 antibody, it remodels the immunosuppressive tumor microenvironment, achieves concurrent sonodynamic‐triggered immune activation, and eradicates both the original and distant‐metastasized tumors efficiently. This work not only provides a new strategy to construct potent sonosensitizers from pyridine‐metal coordination structures but also proves that sonosensitizers with high performance are crucial in boosting cancer sono‐immunotherapy. [ABSTRACT FROM AUTHOR]

Traditional high‐dose antibiotic treatments of intracellular methicillin‐resistant staphylococcus aureus (MRSA) are highly inefficient and associated with a high rate of infection relapse. As an effective antibacterial technology, sonodynamic therapy (SDT) may be able to break the dilemma. However, indiscriminate reactive oxygen species (ROS) release leads to potential side effects. This study incorporates Staphylococcal Protein A antibody‐modified Cu2+/tetracarboxyphenylporphyrin nanoparticles (Cu(II)NS‐SPA) into hydrogel microspheres (HAMA@Cu(II)NS‐SPA) to achieve precise eradication of intracellular bacteria. This eradication is under bioorthogonal activation mediated by bacillithiol (BSH) (internally) and ultrasound (US) (externally). To specify, the US responsiveness of Cu(II)NS‐SPA is restored when it is reduced to Cu(I)NS‐SPA by the BSH secreted characteristically by intracellular MRSA, thus forming a bioorthogonal activation with the external US, which confines ROS production within the infected MΦ. Under external US activation at 2 W cm−2, over 95% of intracellular MRSA can be cleared. In vivo, a single injection of HAMA@Cu(II)NS‐SPA achieves up to two weeks of antibacterial sonodynamic therapy, reducing pro‐inflammatory factor expression by 90%, and peri‐implant bone trabeculae numbers exceed the control group by five times. In summary, these micro/nano hydrogel microspheres mediated by internal and external bioorthogonal activation can precisely eliminate intracellular MRSA, effectively treating multi‐drug resistant intracellular bacterial infections. [ABSTRACT FROM AUTHOR]

The heterogeneity and immunosuppression microenvironment of ovarian cancer seriously restrict the efficiency of monomodal treatment. Emerging multimodal therapy strategies based on sonodynamic therapy with enhanced antitumor effects have attracted intensive attention in the quest to combat cancer. However, exploring highly efficient sonosensitizers integrating chemodynamic/sonodynamic/immunotherapies with reversing immunosuppressive tumor microenvironment (TME) capacity is urgently desired but remains challenging. Here, a facile strategy is designed to synthesize immunomodulating sonocatalytic nanoagents (IrT‐SCN) with dual‐functional Ir‐N centers and narrow bandgap for reversing immunosuppression and potentiating ovarian cancer immunotherapy. IrT‐SCN with dual‐functional centers Ir‐N2 and Ir‐N4 and conjugated networks show a reduced bandgap, moderate interaction with H2O2, and efficient production of reactive oxygen species (ROS). Such ROS capabilities include: 1) utilizing H2O2 in TME to catalytically generate potent O2, as well as abundant superoxide anion (•O2−) and singlet oxygen (1O2) radicals; 2) external ultrasound (US) irradiation can also boost the production of 1O2 simultaneously; 3) M1 polarization of tumor‐associated macrophages and enhanced immune effect can promote the outcome of cancer treatment. This finding provides proof‐of‐concept evidence for the future development of immunomodulating sonocatalytic nanoagents for oncological treatments and other ROS‐related biomedical fields. [ABSTRACT FROM AUTHOR]

A novel ferrocene conjugated Mn(I)‐tricarbonyl complex viz [Mn(Fc‐tpy)(CO)3Br] (Mn2) where, Fc‐tpy=4′‐ferrocenyl‐2,2′:6′,2′′‐terpyridine was synthesized and fully characterized along with its non‐ferrocene analog [Mn(Ph‐tpy)(CO)3Br] Ph‐tpy=4′‐phenyl‐2,2′:6′,2′′‐terpyridine (Mn1) for ultrasound (US) activated anticancer applications. The X‐ray structure of Mn2 confirmed its distorted octahedral geometry. Mn1 and Mn2, for the first time, showed US‐triggered release of CO and ROS generation (1O2 and ⋅OH) in an aqueous solution from any Mn(I)‐tricarbonyl complexes, indicating its potential for synergetic CO gas therapy and sonodynamic therapy. The above‐mentioned in‐solution chemistry was successfully translated into in vitro cellular models. These complexes showed unprecedented US‐triggered toxicity against T‐cell lymphoma and human breast cancer cells (IC50 for Mn2<1 μM) while were minimally toxic without US or against normal spleen and human embryonic kidney cells. Mn2 was ca. 12 fold more anticancer active than Mn1, indicating that the ferrocene conjugation augmented the US sensitivity. The apoptotic sonotoxicity of Mn2 was due to US‐promoted mitochondrial depolarization via ROS generation and CO release. The apoptosis was triggered by caspase 3 activation. This is the first report of Mn(I)‐tricarbonyl‐based sonosensitizers for cancer SDT. Overall, this study, for the first time, establishes the effectiveness of 3d metal carbonyls in SDT. [ABSTRACT FROM AUTHOR]

Sonodynamic therapy (SDT) is promising for combating deep‐seated infectious diseases by generating substantial reactive oxygen species (ROS) through the profound tissue penetration capabilities of ultrasound. However, the compact protective structures of bacterial biofilms present a formidable challenge, impeding ROS efficacy. Given that ROS have a limited diffusion range and current sonosensitizers struggle to infiltrate biofilms, complete eradication of pathogenic bacteria often remains unachieved. In this study, mesoporous titanium dioxide (TiO2) nanoparticles are engineered asymmetrically coated with a thin layer of Ag and loaded with L‐arginine (LA) to construct ultrasound‐propelled nanomotors. These Ag‐TiO2‐LA Janus nanoparticles demonstrate robust self‐propulsion upon ultrasonic activation, allowing for deeper penetration into biofilm matrices and enhancing localized biofilm disruption through improved SDT outcomes. Additionally, the incorporation of Ag not only broadens TiO2's absorption spectrum but also confers photothermal capabilities upon NIR laser excitation at 808 nm. The Ag‐TiO2‐LA nanomotor amalgamates TiO2's sonodynamic potential with Ag's photothermal properties, forging a versatile antimicrobial agent capable of efficient biofilm penetration and a synergistic antibacterial effect when subjected to dual NIR and ultrasound stimuli. This innovative, singularly‐structured nanoparticle stands out as an effective combatant against bacterial biofilms and accelerates the healing process of infected wounds, showcasing potential for multifaceted clinical applications. [ABSTRACT FROM AUTHOR]

The strategy of in vivo self‐assembly has been developed for improved enrichment and long‐term retention of anticancer drug in tumor tissues. However, most self‐assemblies with non‐covalent bonding interactions are susceptible to complex physiological environments, leading to weak stability and loss of biological function. Here, we develop a coupling‐induced assembly (CIA) strategy to generate covalently crosslinked nanofibers, which is applied for in situ constructing artificial shell on mitochondria. The oxidation‐responsive peptide‐porphyrin conjugate P1 is synthesized, which self‐assemble into nanoparticles. Under the oxidative microenvironment of mitochondria, the coupling of thiols in P1 causes the formation of dimers, which is further ordered and stacked into crosslinked nanofibers. As a result, the artificial shell is constructed on the mitochondria efficiently through multivalent cooperative interactions due to the increased binding sites. Under ultrasound (US) irradiation, the porphyrin molecules in the shell produce a large amount of reactive oxygen species (ROS) that act on the adjacent mitochondrial membrane, exhibiting ~2‐fold higher antitumor activity than nanoparticles in vitro and in vivo. Therefore, the mitochondria‐targeted CIA strategy provides a novel perspective on improved sonodynamic therapy (SDT) and shows potential applications in antitumor therapies. [ABSTRACT FROM AUTHOR]

Owing to the dense extracellular matrix and high interstitial fluid pressure in the tumor microenvironment, methods which enhance the permeation and retention of nano drugs into liver tumors remain unsatisfactory for successful tumor treatment. We designed a near-infrared (NIR)- and ultrasound (US)-triggered Pt/Pd-engineered "cluster bomb" (Pt/Pd-CB) which actively penetrates liver cancer cell membranes and achieves photothermal and sonodynamic therapy (SDT). The physical forces generated by the fast expansion and collapse of perfluoropentane nanodroplets eject "sub bombs" (Pt/Pd nanoalloys) into liver cancer cells upon activation by NIR and US. Pt/Pd nanoalloys can then convert H 2 O 2 into O 2 to alleviate hypoxia and boost SDT efficiency while exhibiting a highly efficient photothermal response under NIR irradiation. Our findings might especially be promising for the treatment of solid tumors. [Display omitted] [ABSTRACT FROM AUTHOR]

Point-of-care ultrasound demonstrates significant potential in biomedical research due to its noninvasive, real-time visualization, cost-effectiveness, and other biological benefits. Ultrasound irradiation can precisely control the mechanical and physicochemical effects on pathogenic lesions, enabling real-time visualization, tunable tissue penetration depth, and therapeutic applications. This review summarizes recent advancements in ultrasound-enabled diagnostics and therapeutics, focusing on mechanochemical effects that can be directly integrated into biomedical applications. Additionally, the structure-functionality relationships of sonotheranostic nanoplatforms are systematically discussed, providing insights into the underlying biological effects. Finally, the limitations of current ultrasonic medicine are discussed, along with potential expansions to facilitate patient-centered translations. This review summarizes the recent progress in the development of ultrasound-derived systems for ultrasonic molecular bioimaging and ultrasound-activatable therapy, with deep insights into the action mechanism, clinical challenges, and corresponding remedies. [Display omitted] [ABSTRACT FROM AUTHOR]

Ultrasound-triggered sonodynamic therapy (SDT), with high safety and acceptance, has become a promising tumor treatment. However, the dense stroma, hypoxic microenvironment of tumor, and the unpredictable treatment timing limit the effectiveness of sonosensitizers and the antitumor therapeutic effect. Thus, it is crucial to develop an imaging-guided sensitization strategy for hypoxic tumor sonosensitization to improve the efficacy of SDT. In this study, we developed a biohybrid system CB@HPP, which genetically engineered bacteria to express catalase (CB) and modified nanosonosensitizers (HPP) to the surface of these bacteria. Tumor hypoxia relief, tumor targeting, biocompatibility, and antitumor efficacy were evaluated through in vitro and in vivo experiments. In addition, the photoacoustic (PA), ultrasound (US), and fluorescence (FL) imaging effects of CB@HPP were evaluated in vivo and in vitro. After intravenous injection, CB@HPP was able to target tumor tissue. CB@HPP possessed efficient catalase activity and successfully degraded hydrogen peroxide to produce oxygen. Increased oxygen levels relief intratumoral hypoxia, thereby enhancing CB@HPP-mediated. In addition, CB@HPP showed FL/PA/US multimodal imaging capabilities, which reflects the aggregation effect of CB@HPP in the tumor and suggest the timing of treatment. The biohybrid system CB@HPP significantly alleviates tumor hypoxia, and multimodal imaging-mediated oxygen-producing SDT effectively suppresses tumors. This integrated imaging and therapeutic biohybrid system provides a more efficient and attractive cancer treatment strategy for SDT. This study developed a sensitizing SDT strategy for imaging-guided drug-targeted delivery and in situ oxygen production. We designed a biohybrid system CB@HPP, which was hybridized by the engineered bacteria with catalytic oxygen production and nanosonosensitizer with multimodal imaging capability. CB@HPP significantly alleviates tumor hypoxia, and multimodal imaging-mediated oxygen-producing SDT effectively suppresses tumors. This integrated imaging and therapeutic biohybrid system provides a more efficient and attractive cancer treatment strategy for SDT. [Display omitted] [ABSTRACT FROM AUTHOR]

Despite its effectiveness in exterminating tumor cells, ferroptosis is seriously hampered by the high expression of antioxidant glutathione (GSH) and the inadequacy of endogenous H2O2 in tumors. Herein, metal‐phenolic nanoformulations (FNCP NFs) composed of sonosensitizer Chlorin e6 (Ce6), the phenolic GSH consumer naphthazarin, and Fe3+, followed by the modification of PEG2000, are strategically designed and fabricated for ultrasound‐boosted ferroptosis in tumor cells through triple regulatory pathways. The carrier‐free FNCP NFs can rapidly dissociate under tumor microenvironment response with the assistance of ultrasound, releasing Fe2+, Ce6, and naphthazarin. Ce6 and Fe2+ are capable of producing singlet oxygen (1O2) and hydroxyl radicals (·OH) by ultrasound‐activated sonodynamic therapy and Fenton reaction‐mediated chemodynamic therapy (CDT), respectively, which not only induce apoptotic cell death but also lead to the effective accumulation of lipid peroxidation (LPO), resulting in ferroptosis. Meanwhile, the released naphthazarin and the self‐cycling valence alternations of Fe3+/Fe2+ promote the significant decrease of intracellular GSH contents, further inducing the inactivation of glutathione peroxidase 4 (GPX4) and the up‐regulation of LPO levels, eventually realizing the synergistically enhanced ferroptosis. This facile and feasible design for versatile metal‐phenolic nanoformulations offers a new strategy for effectively improving ferroptosis efficiency and multimodal cancer therapies. [ABSTRACT FROM AUTHOR]

Dynamic tumor therapies (mainly including photodynamic therapy (PDT) and sonodynamic therapy (SDT)) offer new approaches to cancer treatment. They are often characterized by their noninvasive nature, high selectivity, and low toxicity. Sensitizers are crucial for dynamic therapy. Developing efficient sensitizers with good biocompatibility and controllability is an important aim in dynamic therapy. Porphyrins and metalloporphyrins attract great attention due to their excellent photophysical properties and low cytotoxicity under non-light. Compared to porphyrins, metalloporphyrins show greater potential for dynamic therapy due to their enhanced photochemical and photophysical properties after metal ions coordinate with porphyrin rings. This paper reviews some metalloporphyrin-based sensitizers used in photo/sonodynamic therapy and combined therapy. In addition, the probable challenges and bottlenecks in clinical translation are also discussed. [ABSTRACT FROM AUTHOR]

Sonodynamic therapy (SDT) has garnered significant attention in cancer treatment, however, the low-yield reactive oxygen species (ROS) generation from sonosensitizers remains a major challenge. In this study, titanium boride nanosheets (TiB 2 NSs) with photo-enhanced sonodynamic efficiency was fabricated for SDT of glioblastoma (GBM). Compared with commonly-used TiO 2 nanoparticles, the obtained TiB 2 NSs exhibited much higher ROS generation efficiency under ultrasound (US) irradiation due to their narrower band gap (2.50 eV). Importantly, TiB 2 NSs displayed strong localized surface plasmon resonance (LSPR) effect in the second near-infrared (NIR II) window, which facilitated charge transfer rate and improved the separation efficiency of US-triggered electron–hole pairs, leading to photo-enhanced ROS generation efficiency. Furthermore, TiB 2 NSs were encapsulated with macrophage cell membranes (CM) and then modified with RGD peptide to construct biomimetic nanoagents (TiB 2 @CM-RGD) for efficient blood-brain barrier (BBB) penetrating and GBM targeting. After intravenous injection into the tumor-bearing mouse, TiB 2 @CM-RGD can efficiently cross BBB and accumulate in the tumor sites. The tumor growth was significantly inhibited under simultaneous NIR II laser and US irradiation without causing appreciable long-term toxicity. Our work highlighted a new type of multifunctional titanium-based sonosensitizer with photo-enhanced sonodynamic efficiency for GBM treatment. Titanium boride nanosheets (TiB 2 NSs) with photo-enhanced sonodynamic efficiency was fabricated for SDT of glioblastoma (GBM). The obtained TiB 2 NSs displayed strong localized surface plasmon resonance (LSPR) effect in the second near-infrared (NIR II) window, which facilitated charge transfer rate and improved the separation efficiency of US-triggered electron-hole pairs, leading to photo-enhanced ROS generation efficiency. Furthermore, TiB 2 NSs were encapsulated with macrophage cell membranes (CM) and then modified with RGD peptide to construct biomimetic nanoagents (TiB 2 @CM-RGD) for efficient blood-brain barrier (BBB) penetrating and GBM targeting. After intravenous injection into the tumor-bearing mouse, TiB 2 @CM-RGD can efficiently cross BBB and accumulate in the tumor sites. The tumor growth was significantly inhibited under simultaneous NIR II laser and US irradiation without causing appreciable long-term toxicity. [Display omitted] [ABSTRACT FROM AUTHOR]

Malignant glioma remains one of the most aggressive intracranial tumors with devastating clinical outcomes despite the great advances in conventional treatment approaches, including surgery and chemotherapy. Spatio-temporally controllable approaches to glioma are now being actively investigated due to the preponderance, including spatio-temporal adjustability, minimally invasive, repetitive properties, etc. External stimuli can be readily controlled by adjusting the site and density of stimuli to exert the cytotoxic on glioma tissue and avoid undesired injury to normal tissues. It is worth noting that the removability of external stimuli allows for on-demand treatment, which effectively reduces the occurrence of side effects. In this review, we highlight recent advancements in drug delivery systems for spatio-temporally controllable treatments of glioma, focusing on the mechanisms and design principles of sensitizers utilized in these controllable therapies. Moreover, the potential challenges regarding spatio-temporally controllable therapy for glioma are also described, aiming to provide insights into future advancements in this field and their potential clinical applications. [ABSTRACT FROM AUTHOR]

Sonodynamic therapy (SDT), as a promising non‐invasive therapeutic modality combining ultrasound (US) and sonosensitizers to produce cytotoxic reactive oxygen species (ROS) for treating deep‐seated tumors, has received increasing attention in recent years. Porphyrins are multifunctional organic materials, which can be excited both by light and US to produce ROS and possess various fascinating features, including controllable synthetic processes, excellent biodegradability, low cytotoxicity without light or US. Nevertheless, their poor water solubility, skin‐photosensitive toxicity, and insufficient target specificity hinder their clinical applications as sonosensitizer. Although the target specificity issue may be improved by using nanoparticle carriers, and the SDT efficacy can be enhanced by combining with other therapeutic modalities, such combination therapy makes it more confusing about the true mechanism of SDT. This review will focus on the following points: 1) Why are porphyrin‐based sonosensitizers considered the most promising sonosensitizer for clinical applications of SDT? 2) Recent progress in the development of multifunctional porphyrin‐based sonosensitizers. 3) What new insight has been gained on the mechanism of SDT in recent years? 4) The development trend of designing more efficient multifunctional porphyrin‐based sonosensitizers and existing challenges. Finally, future perspective of practical clinical applications of SDT based on multifunctional porphyrin‐based sonosensitizers will be discussed. [ABSTRACT FROM AUTHOR]

[Display omitted] Due to their rigid π-conjugated macrocyclic structure, organic sonosensitizers face significant aggregation in physiological conditions, hindering the production of reactive oxygen species (ROS). An acid-sensitive nanoassembly was developed to address this issue and enhance sonodynamic therapy (SDT) and emission. Initially, copper phthalocyanine (CuPc) was activated using a H 2 SO 4 -assisted hydrothermal method to introduce multiple functional groups (–COOH, –OH, and −SO 3 H), disrupting strong π–π stacking and promoting ROS generation and emission. Subsequently, negatively charged CuPc-SO 4 was incorporated into bovine serum albumin (BSA) to form CuPc-Fe@BSA nanoparticles (10 nm) with Fe3+ ions serving as linkers. In acidic conditions, protonation of CuPc-SO 4 and BSA weakened the interactions, leading to Fe3+ release and nanostructure dissociation. Protonated CuPc-SO 4 tended to self-aggregate into nanorods. This acidity-sensitive aggregation is vital for achieving specific accumulation within the tumor microenvironment (TME), thereby enhancing retention and SDT efficacy. Prior to this, the nanocomposites demonstrated cycling stability under neutral conditions. Additionally, the released Fe ions exhibited mimicry of glutathione peroxidase and peroxidase activity for chemotherapy (CDT). The synergistic effect of SDT and CDT increased intracellular oxidative stress, causing mitochondrial injury and ferroptosis. Furthermore, the combined therapy induced immunogenic cell death (ICD), effectively activating anticancer immune responses and suppressing metastasis and recurrence. [ABSTRACT FROM AUTHOR]

Yong-Gyu Jeong,1 Joo-Hwan Park,2 Dongwoo Khang1,3,4 1Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999, South Korea; 2Division of Medical Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, College of Medicine, Gachon University, Incheon, 21565, South Korea; 3Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 21999, South Korea; 4Department of Physiology, College of Medicine, Gachon University, Incheon, 21999, South KoreaCorrespondence: Dongwoo Khang, Department of Physiology, College of Medicine, Gachon University, Incheon, 21999, South Korea, Tel +82 32 899 1525, Email dkhang@gachon.ac.kr Joo-Hwan Park, Division of Medical Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University, Incheon, 21565, South Korea, Tel +82-32-460-3229, Email replica1874@gilhospital.comAbstract: The advent of acoustically responsive nanodrugs that are specifically optimized for sonodynamic therapy (SDT) is a novel approach for clinical applications. Examining the therapeutic applications of sono-responsive drug delivery systems, understanding their dynamic response to acoustic stimuli, and their crucial role in enhancing targeted drug delivery are intriguing issues for current cancer treatment. Specifically, the suggested review covers SDT, a modality that enhances the cytotoxic activity of specific compounds (sonosensitizers) using ultrasound (US). Notably, SDT offers significant advantages in cancer treatment by utilizing US energy to precisely target and activate sonosensitizers toward deep-seated malignant sites. The potential mechanisms underlying SDT involve the generation of radicals from sonosensitizers, physical disruption of cell membranes, and enhanced drug transport into cells via US-assisted sonoporation. In particular, SDT is emerging as a promising modality for noninvasive, site-directed elimination of solid tumors. Given the complexity and diversity of tumors, many studies have explored the integration of SDT with other treatments to enhance the overall efficacy. This trend has paved the way for SDT-based multimodal synergistic cancer therapies, including sonophototherapy, sonoimmunotherapy, and sonochemotherapy. Representative studies of these multimodal approaches are comprehensively presented, with a detailed discussion of their underlying mechanisms. Additionally, the application of audible sound waves in biological systems is explored, highlighting their potential to influence cellular processes and enhance therapeutic outcomes. Audible sound waves can modulate enzyme activities and affect cell behavior, providing novel avenues for the use of sound-based techniques in medical applications. This review highlights the current challenges and prospects in the development of SDT-based nanomedicines in this rapidly evolving research field. The anticipated growth of this SDT-based therapeutic approach promises to significantly improve the precision of cancer treatment. Keywords: sonodynamic therapy, ultrasound, synergistic therapy, sonosensitizer, nanomedicine, cancer treatment, acoustic audible wave

A novel multifunctional nanozyme IMMMF loading ICG and oxidative phosphorylation inhibitor metformin (Met) inside hollow MnO 2 nanoparticle with metal-polyphenol networks (MPNs) coatings between Fe3+ and folic acid (FA) immobilized tannic acid was constructed to achieve O 2 -generation/O 2 -economization dually enhanced SDT/CDT synergistic antitumor therapy. [Display omitted] As an emerging therapeutic method, the application of sonodynamic therapy (SDT) is hindered by its intrinsic unsatisfactory efficiency, the tumor hypoxia and low tumor specificity. Here, we reported the design of a tumor-targeting multifunctional nanodrug for O 2 -generation/O 2 -economization dually enhanced SDT/chemodynamic therapy (CDT) combination therapy. After the co-encapsulation of sonosensitizer indocyanine green (ICG) and oxidative phosphorylation inhibitor metformin (Met) into hollow MnO 2 (H-MnO 2) nanoparticles, ICG/Met@H-MnO 2 @MPN-FA (IMMMF) was conveniently prepared through the formation of metal–phenolic networks (MPNs) between Fe3+ and folic acid (FA) immobilized tannic acid (TA, TA-FA) onto its surface. In vitro experiments indicated its selective uptake by 4T1 cells via the specific folate receptors-FA interactions. Responding to glutathione (GSH) and the acidic environment, the decomposition of IMMMF led to the release of Mn2+ and Fe2+ for enhanced CDT, and ICG for SDT. Furthermore, Met was continuously released to reduce O 2 consumption for enhanced SDT. More importantly, IMMMF catalyzed the endogenous H 2 O 2 into O 2 for further enhanced SDT. Expectedly, both in vitro and in vivo antitumor assays confirmed its satisfactory therapeutic efficiency via CDT/SDT synergistic therapy. Hence, this intelligent sonocatalytic nanoagent emerges as a promising candidate for CDT-enhanced SDT, which also provides a novel strategy for dually alleviating tumor hypoxia with better therapy. [ABSTRACT FROM AUTHOR]

[Display omitted] Sonodynamic therapy (SDT) is a minimally invasive therapeutic approach that utilizes sonosensitizers to catalyze substrates and generate reactive oxygen species (ROS) under ultrasound stimulation, ultimately inducing tumor cell death. Enhancing the piezoelectric properties of nanomaterials and modulating the semiconductor energy band are effective strategies to improve the catalytic efficiency of sonosensitizers. In this study, we developed a two-dimensional (2D) copper-based piezoelectric metal–organic framework (MOF) sonosensitizer, denoted as CM, through the coordination of copper and dimethylimidazole. The unique 2D MOF structure imparts CM with piezoelectric characteristics, enabling it to enhance SDT efficacy by modulating the semiconductor bandgap and carrier mobility. Upon ultrasound irradiation, CM catalyzes oxygen to undergo a cascade reaction, producing highly toxic singlet oxygen. Additionally, cupric ions in CM can be reduced by glutathione, facilitating the spontaneous catalysis of hydrogen peroxide in tumors to generate hydroxyl radicals and deplete glutathione, thereby inducing oxidative damage. Moreover, cupric ions in CM can trigger tumor cell cuproptosis, which, in combination with the generated ROS, accelerates cell death. Thus, this study establishes a MOF-based system for controllably inducing multi-pathway cancer cell death and provides a foundation for enhancing ultrasound-catalyzed tumor therapy through the optimization of piezoelectric properties. [ABSTRACT FROM AUTHOR]

The piezoelectric semiconductor acoustic sonosensitiser BMO/PB-Au@CM NPs that integrate superior CAT-like enzyme and special GSHOD-like enzyme into one system to achieve efficient antitumour SDT efficacy. [Display omitted] Deprivation of oxygen and scavenging of reactive oxygen species (ROS) severely restrict the antitumor efficiency of sonodynamic therapy (SDT). To address these challs, we report the Bi 2 MoO 6 /Prussian Blue-Au (BMO/PB-Au) nanosystem as piezoelectric sonosensitiser for highly efficient ROS production under ultrasonic irradiation. In this system, the nanosystem has catalase-like (CAT) and glutathione oxidase (GSHOD) catalytic activity, which can enhance SDT effectively by producing reactive oxygen species and consuming glutathione (GSH). While the narrow bandgap and heterojunctions contribute to the improved charge separation and charge recombination suppression of the piezoelectric semiconductor BMO, accelerating ROS generation. Packaging MCF-7 cancer cell membranes (CM) on the surface of BMO/PB-Au will effectively improve the enrichment of nanoparticles in tumor tissue. The in vivo results showed that the BMO/PB-Au@CM nanoplatform can effectively inhibit tumor growth through the enhanced SDT effect. Our findings provide a paradigm to rationally design hypoxia-relieve and GSH-depleted SDT platform to for promoting cancer therapy efficiency. [ABSTRACT FROM AUTHOR]

[Display omitted] Sonodynamic therapy is a promising, noninvasive, and precise tumor treatment that leverages sonosensitizers to generate cytotoxic reactive oxygen species during ultrasound stimulation. Gallic acid (GA), a natural polyphenol, possesses certain anti-tumor properties, but exhibits significant toxicity toward normal cells, limiting its application in cancer treatment. To overcome this issue, we synthesized a bismuth-gallic acid (BGA), coordinated metal–organic framework (MOF) nano-prodrug. Upon encountering glutathione (GSH), BGA gradually dissociated and depleted GSH, releasing GA, which had anti-tumor effects. As an MOF with semiconductor properties, BGA primarily produced superoxide anion radical upon ultrasound excitation. After the release of GA, GA generated superoxide anion radical and further produced high toxic singlet oxygen under ultrasound stimulation, while further oxidizing and consuming GSH, enhancing sonocatalytic performance. Additionally, the released GA induced cell cycle arrest, ultimately leading to apoptosis. Our results revealed that BGA, as a GSH-activated, metal-polyphenol MOF nano-prodrug, showed potential for use in breast tumor sonodynamic therapy, providing a novel strategy for precise tumor treatment. [ABSTRACT FROM AUTHOR]

Hongwei Xiang,&ast; Bin Shen,&ast; Chunmei Zhang, Rui Li Department of Ultrasound, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Rui Li, Email raylee7991@hospital.cqmu.edu.cnIntroduction: Cell death regulation holds a unique value in the field of cancer therapy. Recently, disulfidptosis has garnered substantial scientific attention. Previous studies have reported that sonodynamic therapy (SDT) based on reactive oxygen species (ROS) can regulate cancer cell death, achieving an limited anti-cancer effect. However, the integration of SDT with disulfidptosis as an anti-cancer strategy has not been extensively developed. In this study, we constructed an artificial membrane disulfidptosis sonosensitizer, specifically, a nanoliposome (SC@lip) coated with a combination of the chemotherapy medicine Sorafenib (Sora) and sonosensitizer Chlorin e6 (Ce6), to realize a one-stop enhanced SDT effect that induces disulfidptosis-like cancer cell death.Methods: Sorafenib and Ce6 were co-encapsulated into PEG-modified liposomes, and SC@Lip was constructed using a simple rotary evaporation phacoemulsification method. The cell phagocytosis, ROS generation ability, glutathione (GSH) depletion ability, lipid peroxidation (LPO), and disulfidptosis-like death mediated by SC@Lip under ultrasound (US) irradiation were evaluated. Based on a 4T1 subcutaneous tumor model, both the in vivo biological safety assessment and the efficacy of SDT were assessed.Results: SC@Lip exhibits high efficiency in cellular phagocytosis. After being endocytosed by 4T1 cells, abundant ROS were produced under SDT activation, and the cell survival rates were below 5%. When applied to a 4T1 subcutaneous tumor model, the enhanced SDT mediated by SC@Lip inhibited tumor growth and prolonged the survival time of mice. In vitro and in vivo experiments show that SC@Lip can enhance the SDT effect and trigger disulfidptosis-like cancer cell death, thus achieving anti-tumor efficacy both in vitro and in vivo.Conclusion: SC@Lip is a multifunctional nanoplatform with an artificial membrane, which can integrate the functions of sonosensitization and GSH depletion into a biocompatible nanoplatform, and can be used to enhance the SDT effect and promote disulfidptosis-like cancer cell death.Keywords: disulfidptosis, sonodynamic therapy, reactive oxygen species, liposomes, lipid peroxidation

Ting Dai,&ast; Qimeihui Wang,&ast; Lingyu Zhu, Qiang Luo, Jiayu Yang, Xia Meng, Hui Wang, Zhixia Sun Department of Ultrasound, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hui Wang; Zhixia Sun, Department of Ultrasound, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, 130033, People’s Republic of China, Email whui66@jlu.edu.cn; sunzx@jlu.edu.cnIntroduction: The effective accumulation of nanoparticles (NPs) in the tumour area is an important goals of current nanotechnology research, and a targeted nanoplatform is an effective solution. So we designed a multifunctional sound-sensitive targeted NP that combines a sonosensitizer to enable precisely targeted, deep-penetration sonodynamic therapy (SDT) in combination with multimodal imaging for the diagnosis and monitoring of renal cell carcinoma (RCC).Methods: ZnPP@PP NPs (ZnPP@PLGA- PFP NPs) were prepared via a double emulsion method, and G250 was covalently attached to the NPs shell via the carbon diimide method. Physicochemical property tests were conducted on the ZnPP@G-PP NPs, including tests of particle size, potential distribution, encapsulation efficiency and drug loading capability. We assessed the targeting ability, the production of reactive oxygen species (ROS) and permeability of the NPs in vitro. Moreover, we evaluated the nanoparticle’s multimodal imaging capabilities and therapeutic ability against RCC, both in vitro and in vivo.Results: The Znpp@G-PP NPs were successfully constructed, and their general properties showed uniform particle size, negative potential and good stability. The nanoparticles were successfully loaded with ZnPP and connected with G250, showing tumor-specific targeting ability. Under LIFU irradiation, the nanoparticles produced 1O2 by SDT. For RCC, PA/US multi-modal imaging of Znpp@G-PP NPs provide diagnostic information and monitor therapies in real time in 786-O RCC xenografts, with good biocompatibility. With the UTMD, nanoparticles can be effectively targeted into the tumor cells and penetrate into the tumor interior, significantly improving the SDT effect. Experiments in vitro and in vivo showed that the combination of the nanoparticles and LIFU could suppress the tumor, and the therapeutic effect was confirmed by immunohistochemistry.Conclusion: ZnPP@G-PP NPs provide a promising theranostic strategy for RCC and a platform for further research on improving the efficacy of diagnosis and treatment.Keywords: targeted therapy, deep-penetration, sonodynamic therapy, multimodal imaging

Hailing Yu,1,&ast; Yongquan Huang,2,&ast; Zhisheng Nong,3,&ast; Xi Lin,1 Kexin Tang,1 Zeyu Cai,1 Kaichen Huang,4 Ting Yu,1 Huimin Lan,1 Qianqian Zhang,1 Qiang Wang,5 Lei Yang,6 Jingchuan Zhu,7 Lili Wu,8 Hui Luo1 1Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong, People’s Republic of China; 2Department of Ultrasound, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, People’s Republic of China; 3School of Materials Science and Engineering, Shenyang Aerospace University, Shenyang, Liaoning, People’s Republic of China; 4Department of Clinical laboratory, The Third People’s Hospital of Zhuhai, Zhuhai, Guangdong, People’s Republic of China; 5The Green Aerotechnics Research Institute of Chongqing Jiaotong University, Chongqing, People’s Republic of China; 6Center for Composite Materials and Structures, Harbin Institute of Technology, Harbin, Heilongjiang, People’s Republic of China; 7School of Materials Science and Engineering, Harbin Institute of Technology, Harbin, Heilongjiang, People’s Republic of China; 8Key Laboratory for Photonic and Electronic Bandgap Materials, Ministry of Education, School of Physics and Electronic Engineering, Harbin Normal University, Harbin, Heilongjiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hui Luo; Lili Wu, Email luoh53@mail.sysu.edu.cn; wll790107@hotmail.comIntroduction: Traditional cancer treatment strategies often have severe toxic side effects and poor therapeutic efficacy. To address the long-standing problems related to overcoming the complexity of tumors, we develop a novel nanozyme based on the in situ oxidation of 2D Ti3C2 structure to perform simultaneous phototherapy and sonodynamic therapy on tumors. Ti3C2 nanozymes exhibit multi-enzyme activity, including intrinsic peroxidase (POD) activities, which can react with H2O2 in the tumor microenvironment. This new material can construct Ti3C2/TiO2 heterostructures in vivo.Methods: Photothermal (PTT), sonodynamic (SDT) effects, and photoacoustic (PA) image-guided synergy therapy can be achieved. Finally, anticancer immune responses occur with this nanozyme. In vivo experiments revealed that the Ti3C2/TiO2 heterostructure inhibited tumor growth.Results: Complementarily, our results showed that the Ti3C2/TiO2 heterostructure enhanced the immunogenic activity of tumors by recruiting cytotoxic T cells, thereby enhancing the tumor ablation effect. Mechanistic studies consistently indicated that Reactive Oxygen Species (ROS) regulates apoptosis of HCC cells by modulating NRF2/OSGIN1 signaling both in vitro and in vivo. As a result, Ti3C2 nanozyme effectively inhibited tumor through its synergistic ability to modulate ROS and enhance immune infiltration of cytotoxic T cells in the tumor microenvironment.Discussion: These findings open up new avenues for enhancing 2D Ti3C2 nanosheets and suggest a new way to develop more effective sonosensitizers for the treatment of cancer.Keywords: nanozyme, sonodynamic therapy, Ti3C2/TiO2, ROS

Meng Wei,1,2,&ast; Xiaobo Wang,1,2,&ast; Yunhai Mo,1,2,&ast; Cunqing Kong,3 Mengqi Zhang,2,4 Guanhua Qiu,2,5 Zhihong Tang,1,2 Jie Chen,1,2 Feixiang Wu1,2 1Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, 530021, People’s Republic of China; 2Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education/Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Nanning, 530021, People’s Republic of China; 3Medical Imaging Center, Affiliated Taihe Hospital, Hubei University of Medicine, Hubei, 442000, People’s Republic of China; 4Department of Interventional Therapy, Guangxi Medical University Cancer Hospital, Nanning, 530021, People’s Republic of China; 5Department of Ultrasound, Guangxi Medical University Cancer Hospital, Nanning, 530021, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jie Chen; Feixiang Wu, Email jiechen185@163.com; wufx2013@163.comIntroduction: Current therapeutic strategies, including immune checkpoint blockade (ICB), exhibit limited efficacy in treating hepatocellular carcinoma (HCC). Nanoparticles, particularly those that can accumulate specifically within tumors and be activated by sonodynamic therapy (SDT), can induce immunogenic cell death (ICD); however, ICD alone has not achieved satisfactory therapeutic effectiveness. This study investigates whether combining ICB with ICD induced by nanoparticle-mediated SDT could enhance anti-tumor immunity and inhibit HCC growth.Methods: We developed an iron-based micelle nanodelivery system encapsulating the Near-Infrared Dye IR-780, which was surface-modified with a cyclic tripeptide composed of arginine-glycine-aspartic acid (cRGD). This led to the synthesis of targeted IR780@FOM-cRGD nanoparticles. These nanoparticles were specifically engineered to kill tumor cells under sonication, activate immunogenic cell death (ICD), and be used in conjunction with immune checkpoint blockade (ICB) for the treatment of hepatocellular carcinoma (HCC).Results: The synthesized IR780@FOM-cRGD nanoparticles had an average diameter of 28.23± 1.750 nm and a Zeta potential of − 23.95± 1.926. Confocal microscopy demonstrated that IR780@FOM-cRGD could target HCC cells while minimizing toxicity to healthy cells. Upon sonodynamic activation, these nanoparticles consumed significant amounts of oxygen and generated substantial reactive oxygen species (ROS), effectively killing tumor cells and inhibiting the proliferation, invasion, and migration of H22 cells. Hemolysis assays confirmed the in vivo safety of the nanoparticles, and in vivo fluorescence imaging revealed significant accumulation in tumor tissues. Mouse model experiments showed that combining ICB(which induced by Anti-PD-L1) with ICD (which induced by IR780@FOM-cRGD), could effectively activated anti-tumor immunity and suppressed tumor growth.Discussion: This study highlights the potential of IR780@FOM-cRGD nanoparticles to facilitate tumor eradication and immune activation when used in conjunction with Anti-PD-L1 therapy. This combination represents a non-invasive, efficient, and targeted approach for the treatment of hepatocellular carcinoma (HCC). By integrating sonodynamic therapy with immunotherapy, this strategy promises to substantially improve the effectiveness of traditional treatments in combating HCC, offering new avenues for clinical application and therapeutic innovation.Keywords: nanomaterials, sonodynamic therapy, tumor immunity, PD-L1, immunogenic cell death

Abstract Background Ovarian cancer (OC) has the highest fatality rate among all gynecological malignancies, necessitating the exploration of novel, efficient, and low-toxicity therapeutic strategies. Ferroptosis is a type of programmed cell death induced by iron-dependent lipid peroxidation and can potentially activate antitumor immunity. Developing highly effective ferroptosis inducers may improve OC prognosis. Results In this study, we developed an ultrasonically controllable two-dimensional (2D) piezoelectric nanoagonist (Bi2MoO6-MXene) to induce ferroptosis. A Schottky heterojunction between Bi2MoO6 (BMO) and MXene reduced the bandgap width by 0.44 eV, increased the carrier-separation efficiency, and decreased the recombination rate of electron–hole pairs under ultrasound stimulation. Therefore, the reactive oxygen species yield was enhanced. Under spatiotemporal ultrasound excitation, BMO-MXene effectively inhibited OC proliferation by more than 90%, induced lipid peroxidation, decreased mitochondrial-membrane potential, and inactivated the glutathione peroxidase and cystathionine transporter protein system, thereby causing ferroptosis in tumor cells. Ferroptosis in OC cells further activated immunogenic cell death, facilitating dendritic cell maturation and stimulating antitumor immunity. Conclusion We have succeeded in developing a highly potent ferroptosis inducer (BMO-MXene), capable of inhibiting OC progression through the sonodynamic-ferroptosis-immunogenic cell death pathway. Graphical Abstract

Juying Zhang,1 Xia Luo,1 Xin Yang,1 Hanmei Li,1 Qiong Jiang,1 You Yang,1 Menglin Luo,1 Zijun Ma,1 Ping He,1 Linli Feng,1 Ling Li,1 Maochun Zhang,1 Yang Li,2,3 Jinhong Yu1,3 1Department of Ultrasound, Affiliated Hospital of North Sichuan Medical College, Innovation Centre for Science and Technology of North Sichuan Medical College, Nanchong, Sichuan, 637000, People’s Republic of China; 2Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, 637000, People’s Republic of China; 3Department of Ultrasound, Yuechi People’s Hospital, Guangan, Sichuan, 638300, People’s Republic of ChinaCorrespondence: Jinhong Yu, Email yujinhong@nsmc.edu.cnPurpose: The incidence of hepatocellular carcinoma (HCC) is continuously increasing, and the mortality rate remains high. Thus, more effective strategies are needed to improve the treatment of HCC.Methods: In this study, we report the use of a visualized glypican-3 (GPC3)-targeting nanodelivery system (named GC-NBs) in combination with sonodynamic therapy (SDT) to enhance the therapeutic efficacy for treating HCC. The obtained nanodelivery system could actively target hepatocellular carcinoma cells and achieve ultrasound imaging through phase changes into nanobubbles under low-intensity ultrasound irradiation. Meanwhile, the released chlorine e6 (Ce6) after the nanobubbles collapse could lead to the generation of reactive oxygen species (ROS) under ultrasound irradiation to induce SDT.Results: Both in vitro and in vivo experiments have shown that GC-NBs can accumulate in tumour areas and achieve sonodynamic antitumour therapy under the navigation action of glypican-3-antibody (GPC3-Ab). Furthermore, in vitro and in vivo experiments did not show significant biological toxicity of the nanodelivery system. Moreover, GC-NBs can be imaged with ultrasound, providing personalized treatment monitoring.Conclusion: GC-NBs enable a visualized antitumour strategy from a targeted sonodynamic perspective by combining tumour-specific targeting and stimuli-responsive controlled release into a single system. Keywords: Glypican-3, nanodelivery system, ultrasound imaging, sonodynamic therapy, hepatocellular carcinoma

This research commenced with an exploration of how metal nodes in metal‐organic frameworks (MOFs) influence photodynamic therapy (PDT) outcomes. Ultimately, it is revealed that intermolecular interactions are the core mechanism determining the optical properties and PDT efficacy of MOFs. An advanced system of MOFs based on the integration of twelve rare earth ions (RE3+) with boron dipyrromethene (BODIPY)‐derived ligands is reported. Intriguingly, this series of MOFs exhibits a reverse relationship between the radius of RE3+ and PDT efficacy. Single‐crystal X‐ray diffraction analyses along with theoretical calculations indicate that varying RE3+ results in a spatial displacement of the ligands along the dipole direction, diminishing electrostatic (dipole–dipole) interactions while enhancing dispersion (π–π) interactions, thereby enhancing the generation of triplet excitons. Consequently, a novel parameter, Ae‐v = EvdW / Eint × 100%, is proposed to quantify the interplay between non‐radiative energy dissipation via electrostatic interactions and efficient energy utilization in generating singlet oxygen through dispersion interactions. Furthermore, with consistent acoustic sensitivity aligned with the sonoluminescence mechanism, RE‐DCBs are employed in sono‐photodynamic cancer therapy, attaining significant therapeutic results in tumor treatment during in vivo experiments. [ABSTRACT FROM AUTHOR]

Treatment of highly aggressive triple‐negative breast cancer (TNBC) in the clinic is challenging. Here, a liposome nanodrug (LP@PFH@HMME) integrating imaging agents and therapeutic agents for bimodal imaging‐guided sonodynamic therapy (SDT) is developed, which boosted immunogenicity to enable potent immunotherapy via immune checkpoint blockade (ICB) in TNBC. In the acidic tumor microenvironment (TME), LP@PFH@HMME undergoes "nano‐to‐micro" transformation due to a pH‐responsive lipid fusion, which makes droplets much more sensitive to ultrasound (US) in contrast‐enhanced ultrasound (CEUS) and SDT studies. The nanodrug demonstrates robust bimodal imaging ability through fluorine‐19 magnetic resonance imaging (19F MRI) and CEUS bimodal imaging, and it exhibits excellent solubility in aqueous solution with relatively high 19F content and desirable long transverse relaxation time (T2 = 1.072 s), making it suitable for high‐performance 19F MRI, in addition to effective accumulation of nanodrugs after tail vein injection. Thus, 19F MRI/CEUS dual imaging is achievable to show adequate time points for US irradiation of tumor sites to induce highly effective SDT, which produces abundant reactive oxygen species (ROS) triggering immunogenic cell death (ICD) to assist ICB‐based immunotherapy. The combination treatment design of sonodynamic therapy with immunotherapy effectively inhibited TNBC growth and recurrence, highlighting the promise of multifunctional nanodrugs in treating TNBC. [ABSTRACT FROM AUTHOR]

Simple Summary: Recently, sonodynamic therapy (SDT) has emerged as a promising non-invasive approach for treating cancer by activating sensitizers with ultrasound (US). In this context, we investigated C60 fullerene (C60) as a nanocarrier for the promising drug Berberine (Ber)—both potential aromatic sonosensitizers. The preferential mitochondrial accumulation of C60 and the proapoptotic effects of Ber also make the C60-Berberine nanocomplex (C60-Ber) a good candidate for direct induction of the intrinsic apoptotic cell death under US action. The in vitro research on C60-Ber can provide insights into novel, non-invasive cancer treatments. These findings lead to the development of targeted therapies with reduced side effects, inspire interdisciplinary collaboration, and open new avenues for drug delivery and cancer therapy research. Objectives: The primary objective of this research targeted the biochemical effects of SDT on human cervix carcinoma (HeLa) and mouse Lewis lung carcinoma (LLC) cells grown in 2D monolayer and 3D spheroid cell culture. Methods: HeLa and LLC monolayers and spheroids were treated with a 20 µM C60-Ber for 24 h, followed by irradiation with 1 MHz, 1 W/cm2 US. To evaluate the efficacy of the proposed treatment on cancer cells, assessments of cell viability, caspase 3/7 activity, ATP levels, and ROS levels were conducted. Results: Our results revealed that US irradiation alone had negligible effects on LLC and HeLa cancer cells. However, both monolayers and spheroids irradiated with US in the presence of the C60-Ber exhibited a significant decrease in viability (32% and 37%) and ATP levels (42% and 64%), along with a notable increase in ROS levels (398% and 396%) and caspase 3/7 activity (437% and 246%), for HeLa monolayers and spheroids, respectively. Similar tendencies were observed with LLC cells. In addition, the anticancer effects of C60-Ber surpassed those of C60, Ber, or their mixture (C60 + Ber) in both cell lines. Conclusions: The detected intensified ROS generation and ATP level drop point to mitochondria dysfunction, while increased caspase 3/7 activity points on the apoptotic pathway induction. The combination of 1 W/cm2 US with C60-Ber showcased a promising platform for synergistic sonodynamic chemotherapy for cancer treatment. [ABSTRACT FROM AUTHOR]

The first example of sonodynamic therapy (SDT) with a cyanine dye–antibody conjugate is reported. The aim of this study was to evaluate the sonodynamic efficacy of a trastuzumab-guided diiodinated heptamethine cyanine-based sensitizer, 2ICy7–Ab, versus its non-iodinated counterpart, Cy7–Ab, in a human epidermal growth factor receptor 2-positive (HER2+) xenograft model. In addition, the combined sonodynamic and photodynamic (PDT) effects were investigated. A single intravenous injection of 2ICy7–Ab followed by sonication or combined sonication and photoirradiation in mice resulted in complete tumor growth suppression compared with the nontreated control and showed no detectable toxicity to off-target tissues. In contrast, Cy7–Ab provided only a moderate therapeutic effect (~1.4–1.6-fold suppression). SDT with 2ICy7–Ab resulted in a 3.5-fold reduction in tumor volume within 45 days and exhibited 13-fold greater tumor suppression than PDT alone. In addition, 2ICy7–Ab showed more durable sonostability than photostability. The sonotoxicity of the iodinated versus noniodinated counterparts is attributed to the increased generation of hydroxyl radicals, superoxide, and singlet oxygen. We observed no significant contribution of PDT to the efficacy of the combined SDT and PDT, indicating that SDT with 2ICy7–Ab is superior to PDT alone. These new findings set the stage for the application of cyanine–antibody conjugates for fluorescently monitored targeted sonodynamic treatment of cancer. [ABSTRACT FROM AUTHOR]

Background: Intra-axial brain tumors persist as significant clinical challenges. Aggressive surgical resection carries risk of morbidity, and the blood-brain barrier (BBB) prevents optimal pharmacological interventions. There is a clear clinical demand for innovative and less invasive therapeutic strategies for patients, especially those that can augment established treatment protocols. Focused ultrasound (FUS) has emerged as a promising approach to manage brain tumors. Sonodynamic therapy (SDT), a subset of FUS, utilizes sonosensitizers activated by ultrasound waves to generate reactive oxygen species (ROS) and induce tumor cell death. Objective: This review explores the historical evolution and rationale behind SDT, focusing on its mechanisms of action and potential applications in brain tumor management. Method: A systematic review was conducted using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: Preclinical studies have demonstrated the efficacy of various sonosensitizers, including 5-aminolevulinic acid (5-ALA), fluorescein, porphyrin derivatives, and nanoparticles, in conjunction with FUS for targeted tumor therapy and BBB disruption. Clinical trials have shown promising results in terms of safety and efficacy, although further research is needed to fully understand the potential adverse effects and optimize treatment protocols. Challenges such as skull thickness affecting FUS penetration, and the kinetics of BBB opening require careful consideration for the successful implementation of SDT in clinical practice. Future directions include comparative studies of different sonosensitizers, optimization of FUS parameters, and exploration of SDT's immunomodulatory effects. Conclusion: SDT represents a promising frontier in the treatment of aggressive brain tumors, offering hope for improved patient outcomes. [ABSTRACT FROM AUTHOR]

Given that tumor microenvironment (TME) exerts adverse impact on the therapeutic response and clinical outcome, robust TME modulators may significantly improve the curative effect and increase survival benefits of cancer patients. Here, Au nanodots‐anchored CoFe2O4 nanoflowers with PEGylation (CFAP) are developed to respond to TME cues, aiming to exacerbate redox dyshomeostasis for efficacious antineoplastic therapy under ultrasound (US) irradiation. After uptake by tumor cells, CFAP with glucose oxidase (GOx)‐like activity can facilitate glucose depletion and promote the production of H2O2. Multivalent elements of Co(II)/Co(III) and Fe(II)/Fe(III) in CFAP display strong Fenton‐like activity for·OH production from H2O2. On the other hand, energy band structure CFAP is superior for US‐actuated 1O2 generation, relying on the enhanced separation and retarded recombination of e−/h+ pairs. In addition, catalase‐mimic CFAP can react with cytosolic H2O2 to generate molecular oxygen, which may increase the product yields from O2‐consuming reactions, such as glucose oxidation and sonosensitization processes. Besides the massive production of reactive oxygen species, CFAP is also capable of exhausting glutathione to devastate intracellular redox balance. Severe immunogenic cell death and effective inhibition of solid tumor by CFAP demonstrates the clinical potency of such heterogeneous structure and may inspire more relevant designs for disease therapy. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor and known for its challenging prognosis. Sonodynamic therapy (SDT) is an innovative therapeutic approach that shows promise in tumor elimination by activating sonosensitizers with low‐intensity ultrasound. In this study, a novel sonosensitizer is synthesized using Cu‐doped carbon dots (Cu‐CDs) for the sonodynamic treatment of GBM. Doping with copper transforms the carbon dots into a p–n type semiconductor having a bandgap of 1.58 eV, a prolonged lifespan of 10.7 µs, and an improved electron‐ and hole‐separation efficiency. The sonodynamic effect is efficiency enhanced. Western blot analysis reveals that the Cu‐CDs induces a biological response leading to cell death, termed as cuproptosis. Specifically, Cu‐CDs upregulate dihydrosulfanyl transacetylase expression, thereby establishing a synergistic therapeutic effect against tumor cell death when combined with SDT. Furthermore, Cu‐CDs exhibit excellent permeability through the blood‐brain barrier and potent anti‐tumor activity. Importantly, the Cu‐CDs effectively impede the growth of glioblastoma tumors and prolong the survival of mice bearing these tumors. This study provides support for the application of carbon‐based nanomaterials as sonosensitizers in tumor therapy. [ABSTRACT FROM AUTHOR]

Sonodynamic therapy (SDT) has demonstrated considerable potential in its noninvasive approach and ability to target tumors located deep within brain tissues (>10 cm). However, the effectiveness of this technique is hindered by tumor hypoxia (2% O2), the abundance of the reactive oxygen species (ROS) scavenger glutathione (GSH), and the limited ROS generation capacity of the sonosensitizer. In light of these limitations, a cascade nanozyme comprising platinum (Pt)-coated porphyrin metal–organic frameworks (PCN-224-(Fe)) modified with COOH-PEG was developed [Pt/PCN-224-(Fe)/PEG, labeled as PFMP nanozyme] to enhance the toxicity of ROS. This nanozyme emulates the catalytic function of Pt in the decomposition of hydrogen peroxide (H2O2) into O2 for the purpose of alleviating tumor hypoxia. Additionally, it replicates the function of glutathione peroxidase (GPX) by utilizing iron (Fe3+) to reduce the overexpression of GSH. These two mechanisms act in concert to amplify the generation of ROS. They achieve this by enhancing O2 production and impairing the capacity of GSH to scavenge ROS, thereby synergistically potentiating the toxicity of ROS. In vitro and in vivo studies have demonstrated evidence for efficient ROS generation, resulting in a significant 6-fold reduction in tumor volume compared to the control groups and achieving an impressive 80% survival rate 30 days after treatment. [ABSTRACT FROM AUTHOR]

Novel antimicrobial strategies are urgently needed to treat extensively drug‐resistant (XDR) bacterial infections due to the high mortality rate and lack of effective therapeutic agents. Herein, nanoengineered human umbilical cord mesenchymal stem cells (hUC‐MSCs), named PMZMU, are designed as a sonosensitizer for synergistic sonodynamic‐nano‐antimicrobial therapy against gram‐negative XDR bacteria. PMZMU is composed of a bacterial targeting peptide (UBI29‐41) modified hUC‐MSCs membrane (MSCm), a sonosensitizer meso‐tetra(4‐car‐boxyphenyl) porphine doped mesoporous organo‐silica nanoparticle and an acidity‐responsive metal–organic framework ZIF‐8. This innovative formulation enables efficient loading of polymyxin B, reduces off‐target drug release, increases circulation and targeting efficacy, and generates reactive oxygen species upon ultrasound irradiation. PMZMU exhibits remarkable in vitro inhibitory activity against four XDR bacteria: Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa (PA), and Escherichia coli. Taking advantage of the bacterial targeting ability of UBI29‐41 and the inflammatory chemotaxis of hUC‐MSC, PMZMU can be precisely delivered to lung infection sites thereby augmenting polymyxin B concentration. PMZMU‐mediated sonodynamic therapy significantly reduces bacterial burden, relieves inflammatory damage by promoting the polarization of macrophages toward M2 phenotype, and improves survival rates without introducing adverse events. Overall, this study offers promising strategies for treating deep‐tissue XDR bacterial infections, and guides the design and optimization of biomimetic nanomedicine. [ABSTRACT FROM AUTHOR]

Sonography with its non-invasive and deep tissue-penetrating characteristics, not only contributes to promising developments in clinical disease diagnosis but also obtains acknowledgments as a prospective therapeutic approach in the field of tumor treatment. However, it remains a challenge for sonography simultaneously to achieve efficient imaging and therapeutic functionality. Here, we present an innovative integrated diagnosis and treatment paradigm by developing the nanomedicine of percarbamide-bromide-mesoporous organosilica spheres (MOS) with RGD peptide modification (PBMR) by loading percarbamide and bromide in MOS which were prepared by a one-step O/W microemulsion method. The PBMR nanomedicine effectively modifies the tumor acoustic environment to improve sonoimaging efficacy and induces sonochemical reactions to enhance the production of reactive oxygen species (ROS) for tumor treatment efficiency under sonography. The combination of PBMR nanomedicine and SDT achieved multiple ROS generation through the controlled sonochemical reactions and significantly boosted the potency of sonodynamic therapy and induced significant tumor regression with non-invasive tissue penetrability and minimizing damage to healthy tissues. Simultaneously, the generation of oxygen gas in the sonochemical process augments ultrasound reflection, resulting in a 4.9-fold increase in imaging grayscale. Our research establishes an effective platform for the synergistic integration of sonoimaging and sonodynamic antitumor therapy, offering a novel approach for precise antitumor treatment in the potential clinical applications. [ABSTRACT FROM AUTHOR]

Worldwide, two million two hundred thousand new cases of breast cancer were diagnosed in 2020. Traditional breast cancer treatments have several side effects, such as poisoning of the heart and lung during chemotherapy and cardiovascular disease during radiotherapy. Moreover, many patients suffer from acute and chronic pain, loss of breast shape, and limited arm mobility after surgery. Researchers strive to reduce adverse effects by finding more effective strategies. Sonodynamic therapy is a newly developed cancer treatment that offers safety, high penetration depth into soft tissues, accessibility, affordability, etc. In addition to these benefits, sonodynamic therapy also enhances chemotherapy effectiveness. Therefore, the combination of sonodynamic therapy and chemotherapy along with a multifunctional sensitizer can enhance treatment effectiveness while minimizing side effects. In this study, PEGylated gold nanoparticles (PEG-GNPs) were synthesized and loaded with an anticancer agent, Gemcitabine (Gem-PEG-GNPs). The synthesized Gem-PEG-GNPs act as sonosensitizers and nanocarriers, which improve the efficacy of sonodynamic therapy and chemotherapy as well as reduce harmful effects. Ultrasound waves combined with Gem-PEG-GNPs increased apoptosis and decreased survival rates in MCF-7 cells. When Gem-PEG-GNPs and ultrasound waves were combined, a significant synergistic effect was observed compared to ultrasound waves alone. In conclusion, Gem-PEG-GNPs have the potential to be effective sonosensitizers and drug delivery agents in treatment of breast cancer. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) is the most aggressive and lethal subtype of gliomas of the central nervous system. The efficacy of sonodynamic therapy (SDT) against GBM is significantly reduced by the expression of apoptosis‐inhibitory proteins in GBM cells. In this study, an intelligent nanoplatform (denoted as Aza‐BD@PC NPs) based on the aza‐boron‐dipyrromethene dye and phenyl chlorothionocarbonate‐modified DSPE‐PEG molecules is developed for synergistic ferroptosis‐enabled gas therapy (GT) and SDT of GBM. Once internalized by GBM cells, Aza‐BD@PC NPs showed effective cysteine (Cys) consumption and Cys‐triggered hydrogen sulfide (H2S) release for ferroptosis‐enabled GT, thereby disrupting homeostasis in the intracellular environment, affecting GBM cell metabolism, and inhibiting GBM cell proliferation. Additionally, the released Aza‐BD generated abundant singlet oxygen (1O2) under ultrasound irradiation for favorable SDT. In vivo and in vitro evaluations demonstrated that the combined functions of Cys consumption, H2S production, and 1O2 production induced significant death of GBM cells and markedly inhibited tumor growth, with an impressive inhibition rate of up to 97.5%. Collectively, this study constructed a cascade nanoreactor with satisfactory Cys depletion performance, excellent H2S release capability, and prominent reactive oxygen species production ability under ultrasound irradiation for the synergistic ferroptosis‐enabled GT and SDT of gliomas. [ABSTRACT FROM AUTHOR]

Sonodynamic therapy (SDT) has demonstrated significant potential in addressing multidrug‐resistant bacterial infections due to its noninvasive nature and independence from antibiotics and light sources. However, the majority of current sonosensitizers exhibit aggregation‐caused quenching (ACQ), leading to low reactive oxygen species (ROS) generation efficiency. Herein, a novel nonplanar structured sonodynamic (4,4‐difluoro‐4‐boron‐3a,4‐diaza‐indandiene) BODIPY derivative, BODN, with aggregation‐induced emission (AIE) properties, and rapid generation of substantial ROS by ultrasound is introduced. The BODN is co‐assembled with the commercial amphiphilic polymer, mDSPE‐PEG2000, forming BODN nanoparticles (BODN‐NP). Under ultrasound conditions, BODN‐NP demonstrates potent antimicrobial activity and improves the inflammatory response to promote healing wounds infected by both Staphylococcus aureus and methicillin‐resistant Staphylococcus aureus. This work expands the use of AIE sonodynamic materials in antimicrobial therapy and provides new perspectives for innovative solutions against multidrug‐resistant bacterial infections. [ABSTRACT FROM AUTHOR]

It is important but challenging to innovate inorganic sonosensitizers with controlled biodegradability and enhanced sonodynamic and chemodynamic activities to harness and remodel the immunosuppressive tumor microenvironment (TME) for awakening robust immune responses against metastatic cancers. Herein the rational design and defect engineering strategy of a pH‐responsive biodegradable sonozyme system in sulfide nanocages for augmented cancer immunotherapy is reported. A series of highly defective Co9S8‐x sonosensitizers with elevated sulfur‐vacancy (VS) levels are fabricated to systematically explore the VS‐dependent sonodynamic and chemodynamic properties by regulating the weight ratio of the sulfur to cobalt source. The bandgap is substantially reduced from 2.06 to 1.54 eV, and the atomic ratio of Co2+ to Co3+ is increased from 1.53 to 1.97. Therefore, the sonodynamic, chemodynamic, and antitumor immune responses of Co9S8‐x are dramatically augmented by defect engineering of a biodegradable sulfide sonozyme system. The slow degradation in the slightly acid TME substantially reduced the size for enhanced tumor targeting and infiltration, while exerting a slight influence on the sonodynamic performance. As a result, satisfactory therapeutic effects on the eradication of primary, distant, and metastatic tumors can be achieved. This work highlights the potential of defect engineering strategies in biodegradable sonosensitizers for enhanced immunotherapy in combating metastatic cancers. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: Focused ultrasound (FUS) is an innovative and emerging technology for the treatment of adult and pediatric brain tumors and illustrates the intersection of various specialized fields, including neurosurgery, neuro-oncology, radiation oncology, and biomedical engineering. Objective: The authors provide a comprehensive overview of the application and implications of FUS in treating pediatric brain tumors, with a special focus on pediatric low-grade gliomas (pLGGs) and the evolving landscape of this technology and its clinical utility. Methods: The fundamental principles of FUS include its ability to induce thermal ablation or enhance drug delivery through transient blood-brain barrier (BBB) disruption, emphasizing the adaptability of high-intensity focused ultrasound (HIFU) and low-intensity focused ultrasound (LIFU) applications. Results: Several ongoing clinical trials explore the potential of FUS in offering alternative therapeutic strategies for pathologies where conventional treatments fall short, specifically centrally-located benign CNS tumors and diffuse intrinsic pontine glioma (DIPG). A case illustration involving the use of HIFU for pilocytic astrocytoma is presented. Conclusion: Discussions regarding future applications of FUS for the treatment of gliomas include improved drug delivery, immunomodulation, radiosensitization, and other technological advancements. [ABSTRACT FROM AUTHOR]

A multifunctional UIO-66-CoO x sonosensitizer, consisting of amorphous UIO-66 loaded with CoO x , is synthesized to simultaneously induce reactive oxygen species generation and GPX4 deactivation, achieving an augmented therapeutic effect via apoptosis-ferroptosis combination therapy. This work highlights the potential of amorphization engineering in enhancing the efficacy of MOF-based sonosensitizer for combined cancer treatments. [Display omitted] The development of efficient and multifunctional sonosensitizers is crucial for enhancing the efficacy of sonodynamic therapy (SDT). Herein, we have successfully constructed a CoO x -loaded amorphous metal-organic framework (MOF) UIO-66 (A-UIO-66-CoO x) sonosensitizer with excellent catalase (CAT)- and glutathione-oxidase (GSH-OXD)-like activities. The A-UIO-66-CoO x exhibits a 2.6-fold increase in singlet oxygen (1O 2) generation under ultrasound (US) exposure compared to crystalline UIO-66 sonosensitizer, which is attributed to its superior charge transfer efficiency and consistent oxygen (O 2) supply. Additionally, the A-UIO-66-CoO x composite reduces the expression of glutathione peroxidase (GPX4) by depleting glutathione (GSH) through Co3+ and Co2+ valence changes. The high levels of highly cytotoxic 1O 2 and deactivation of GPX4 can lead to lethal lipid peroxidation, resulting in concurrent apoptosis and ferroptosis. Both in vitro and vivo tumor models comprehensively confirmed the enhanced SDT antitumor effect using A-UIO-66-CoO x sonosensitizer. Overall, this study emphasizes the possibility of utilizing amorphization engineering to improve the effectiveness of MOFs-based sonosensitizers for combined cancer therapies. [ABSTRACT FROM AUTHOR]

Sonodynamic therapy (SDT) is emerging as a promising modality for cancer treatment. However, improving the tumor bioavailability and anti-hypoxia capability of sonosensitizers faces a big challenge. In this work, we present a tumor microenvironment (TME)-mediated nanomorphology transformation and oxygen (O 2) self-production strategy to enhance the sonodynamic therapeutic efficacy of tumors. A smart probe Ce6-Leu@Mn2+ that consists of a glutathione (GSH) and leucine amino peptidase (LAP) dual-responsive unit, a 2-cyanobenzothiazole (CBT) group, and a Mn2+-chelated Ce6 as sonosensitizer for tumor SDT was synthesized, and its SDT potential for liver tumor HepG2 in living mice was systematically studied. It was found that the probes could self-assemble into large nanoparticles in physiological condition and spontaneously transformed into small particles under the dual stimulation of GSH and LAP in TME resulting in enhanced tumor accumulation and deep penetration. More notably, Ce6-Leu@Mn2+ could convert endogenous hydrogen peroxide to O 2 , thereby alleviating the hypoxia and achieving effective SDT against hypoxic tumors under the excitation of ultrasound. We thus believe this smart TME-responsive probe may provide a noninvasive and efficient means for malignant tumor treatment. Sonodynamic therapy (SDT) is emerging as a promising therapeutic modality for cancer treatment. However, how to improve the tumor bioavailability and anti-hypoxia capability of sonosensitizers remains a huge challenge. Herein, we rationally developed a theranostic probe Ce6-Leu@Mn2+ that can transform into small-size nanoparticles from initial large particles under the dual stimulation of LAP and GSH in tumor microenvironment (TME) resulting in enhanced tumor accumulation, deep tissue penetration as well as remarkable O 2 self-production for enhanced sonodynamic therapy of human liver HepG2 tumor in living mice. This smart TME-responsive probe may provide a noninvasive and efficient means for hypoxic tumor treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

Sonodynamic therapy (SDT) has been explored for cancer therapy, especially for deep tumors due to its low tissue penetration restriction. The therapeutic efficacy of SDT is limited due to the complicated tumor microenvironment. This study reports the construction of oxygen‐carrying semiconducting polymer nanoprodrugs (OSPNpro) for deep tumor treatment via combining amplified SDT with pyroptosis. An oxygen carrier perfluorohexane, sonodynamic semiconducting polymer as the sonosensitizer, and reactive oxygen species (ROS)‐responsive prodrug are co‐loaded into a nanoparticle system, leading to the formation of these polymer nanoprodrugs. Such OSPNpro show an effective accumulation in tumor tissues after systemic administration, in which they deliver oxygen to relieve tumor hypoxia microenvironment and thus mediate amplified SDT via producing ROS under ultrasound (US) irradiation, even when the tumors are covered with a 2‐cm chicken breast tissue. In addition, the ROS‐responsive prodrugs are activated by the generated ROS to trigger pyroptosis of tumor cells. Such a sono‐pyroptosis induces a strong antitumor immunity with obviously higher level infiltrations of effector immune cells into tumors. Therefore, OSPNpro‐based combinational therapy can greatly inhibit the growth of 2‐cm chicken breast tissue‐covered deep tumors and suppress tumor metastasis. This study offers a prodrug nanoplatform for treatment of deep tumor via sono‐pyroptosis strategy. [ABSTRACT FROM AUTHOR]

The blockade of cytoprotective autophagy has been demonstrated to effectively enhance the efficacy of sonodynamic therapy (SDT). However, the limited recognition of antiautophagy agents for autophagosomes impedes the clinical application of autophagy inhibition. To efficiently deliver hydroxychloroquine (HCQ), an autophagy inhibitor, to autophagosomes, we utilized a strategy based on in situ click chemistry between sulfhydryl (‐SH) and maleimide (Mal) groups to trigger autophagosomes tracking and suppress tumor growth synergistically. A cascade nanoreactor was synthesized by encapsulating Mal‐modified HCQ (MHCQ) into a manganese porphyrin‐based metal‐organic framework with sonosensitizer properties, followed by poly(ethylene glycol)ylated liposomal membrane coating. After ultrasound irradiation, SDT‐induced apoptotic cells released damaged proteins with free ‐SH groups, which MHCQ rapidly captured in situ via a Mal‐thiol click reaction. When autophagosomes actively wrapped damaged proteins for detoxification, they simultaneously internalized HCQ anchored on proteins. In this scenario, antiautophagy drugs could actively track intracellular autophagosomes instead of undergoing passive diffusion in the cytosol. The interaction between HCQ and autophagic vesicles was greatly enhanced, which strengthened the blocking efficiency of autophagy and resulted in complete cell death. Overall, this study with smart design provides a promising strategy for improving intracellular targeted delivery to autophagosomes, thereby enhancing antitumor therapy. [ABSTRACT FROM AUTHOR]