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

Recent Advances in Nanomaterial-Assisted Combinational Sonodynamic Cancer Therapy.

Sonodynamic therapy (SDT) is a new therapeutic method, which can kill malignant tumors by using sonosensitizers and low intensity ultrasound (US) simultaneously. Compared with photo-triggered therapy, SDT exhibits lots of benefits and merits, including high accuracy, deeper tissue penetration, good patient compliance, and fewer side effects. US can penetrate the deep tissues and focus on the tumor areas, thereby activating sonosensitizers, which offers the possibility of non-invasively eradicating solid tumors in a targeted manner. However, the hypoxic tumor microenvironment (TME) and the low quantum yield of sonosensitizers limit the treatment efficiency of SDT. Therefore, it is crucial to improve the sonodynamic effect. In this minireview, we briefly introduce the possible mechanisms of SDT, including the production of reactive oxygen species (ROS), cavitation effect, and hyperthermia destruction. Then we summarize various newly developed strategies to improve the efficacy of SDT through the use of sonosensitizers based on the mechanisms of SDT, providing a theoretical basis for the development of SDT in the future. The strategies to improve the therapeutic efficiency of SDT mainly include: (1) improvement of hypoxia; (2) enhancement of the cavitation effect; (3) consumption of reducing substances (e.g., glutathione, GSH); (4) combination with hypoxia-activated chemotherapeutic drugs; and (5) combination with immunotherapy. In addition, we also focus on the potential strategies of combining SDT with other therapies, and discuss the challenges and limitations of SDT in future clinical applications.

Newly developed strategies for improving sonodynamic therapy

Despite significant advances, the therapeutic impact of photodynamic therapy is still substantially hampered by the restricted penetration depth of light and the reactive oxygen species (ROS)-mediated toxicity, which is impeded by the shorter effective half-life and radius of ROS produced during treatment. Sonodynamic therapy (SDT), on the other hand, provides unrivalled benefits in deep-seated tumour ablation due to its deep penetration depth and not totally ROS-dependent toxicity, exhibiting enormous preclinical and clinical potential. In this tutorial review, we highlight imaging-guided precise SDT, which allows choosing the best treatment option and monitoring the therapy response in real-time, as well as recent clinical trials based on SDT. Aside from that, the subtle design strategies of sonosensitizers based on tumour environment shaping and rational structure modification, as well as SDT combination treatment (chemotherapy, chemodynamic therapy, photodynamic therapy, photothermal therapy, gas therapy and immunotherapy), aimed at a more effective treatment outcome, are summarized. Finally, we discussed the future of SDT for personalized cancer and other disease treatments.

Advanced biotechnology-assisted precise sonodynamic therapy.

The development of highly efficient, multifunctional, and biocompatible sonosensitizer is still a priority for current sonodynamic therapy (SDT). Herein, a defect-rich Ti-based metal-organic framework (MOF) (D-MOF(Ti)) with greatly improved sonosensitizing effect is simply constructed and used for enhanced SDT. Compared with the commonly used sonosensitizer TiO2 , D-MOF(Ti) results in a superior reactive oxygen species (ROS) yield under ultrasound (US) irradiation due to its narrow bandgap, which principally improves the US-triggered electron-hole separation. Meanwhile, due to the existence of Ti3+ ions, D-MOF(Ti) also exhibits a high level of Fenton-like activity to enable chemodynamic therapy. Particularly, US as the excitation source of SDT can simultaneously enhance the Fenton-like reaction to achieve remarkably synergistic outcomes for oncotherapy. More importantly, D-MOF(Ti) can be degraded and metabolized out of the body after completion of its therapeutic functions without off-target toxicity. Overall, this work identifies a novel Ti-familial sonosensitizer harboring great potential for synergistic sonodynamic and chemodynamic cancer therapy.

Conferring Ti-Based MOFs with Defects for Enhanced Sonodynamic Cancer Therapy

Metal-organic frameworks (MOFs) hold great promise for biomedical applications owing to their unique properties. The porous structures make MOFs excellent candidates for the delivery of different drugs; the flexibility in choosing metal ions and organic ligands makes it feasible to prepare MOFs with intrinsic antitumor activities and further devise MOF-drug synergistic systems; many other types of antitumor agents could also be developed using MOFs as the precursors/templates. Thus, the past two decades have witnessed the great development of MOF-based drugs, especially in the antitumor field. This Minireview mainly focuses on the design and applications of MOF-based antitumor agents. Four aspects covering the whole field are introduced: MOFs as carriers, MOFs as antitumor agents, MOF-drug synergistic systems, and MOF-derived antitumor agents. The challenges and opportunities of MOFs for clinical antitumor applications are also discussed.

Antitumor Agents Based on Metal-Organic Frameworks.

The high reactive oxygen species (ROS) generation ability and simple construction of sonosensitizer systems remain challenging in sonodynamic therapy against the hypoxic tumor. In this work, we rationally prepared MOF-derived double-layer hollow manganese silicate nanoparticle (DHMS) with highly effective ROS yield under ultrasound irradiation for multimodal imaging-guided sonodynamic therapy (SDT). The presence of Mn in DHMS increased ROS generation efficiency because it could be oxidized by holes to improve the electron-hole separation. Moreover, DHMS could produce oxygen in the tumor microenvironment, which helps overcome the hypoxia of the solid tumor and thus enhance the treatment efficiency. In vivo experiments demonstrated efficient tumor inhibition in DHMS-mediated SDT guided by ultrasound and magnetic resonance imaging. This work presents a MOF-derived nanoparticle with sonosensitive and oxygen generating ability, which provides a promising strategy for tumor hypoxia in SDT.

MOF-Derived Double-Layer Hollow Nanoparticles with Oxygen Generation Ability for Multimodal Imaging-Guided Sonodynamic Therapy.

Ultrasmall Fe-doped carbon dots nanozymes for photoenhanced antibacterial therapy and wound healing

Manganese carbonate nanoparticles-mediated mitochondrial dysfunction for enhanced sonodynamic therapy

Clinical therapy of multidrug resistant (MDR) bacteria‐induced deep‐tissue infections such as pneumonia is highly challenging. Ultrasound (US)‐induced sonodynamic therapy (SDT) is a promising strategy for treatment of deep‐tissue diseases given the strong tissue penetration of US. Here, ZIF‐8‐derived carbon@TiO2 nanoparticles (ZTNs) are developed as inhalable sonosensitizers for bacterial pneumonia. ZTNs upon US irradiation exhibit an excellent efficacy to produce reactive oxygen species (ROS) and thereby to kill Gram‐negative MDR bacteria in vitro. Taking advantage of aerosolized intratracheal inoculation, ZTNs can be precisely delivered to lung infection sites, and display an effective SDT‐based elimination of Gram‐negative MDR bacteria in the lung infection models of immunocompetent or immunodeficient mice. Particularly, ZTNs upon US irradiation give a 100% survival rate in the severely immunodeficient NOD/SCID mice with a lethal bacterial pneumonia. In addition, ZTNs have no obvious toxicity at both cellular and animal levels. Metal–organic‐framework‐derived nanoparticles as safe and efficient inhalable sonosensitizer have a great potential to be used for the clinical antibiotics‐alternative treatment of MDR bacterial pneumonia. This study presents a new paradigm for SDT‐based treatment of deep‐tissue bacterial infections, and will expand the nanomedicine application of inorganic sonosensitizers.

Juan Guo

Papers

MOF-Derived Double-Layer Hollow Nanoparticles with Oxygen Generation Ability for Multimodal Imaging-Guided Sonodynamic Therapy.

Ultrasmall Fe-doped carbon dots nanozymes for photoenhanced antibacterial therapy and wound healing

Manganese carbonate nanoparticles-mediated mitochondrial dysfunction for enhanced sonodynamic therapy

Inhalable MOF‐Derived Nanoparticles for Sonodynamic Therapy of Bacterial Pneumonia

Molecular Imaging-Guided Sonodynamic Therapy.