Key Takeaways & Executive Findings
- •• SDT combines low-intensity ultrasound and sonosensitizers to generate cytotoxic ROS, offering a non-invasive approach with deep tissue penetration for treating deep-seated tumors. • Nanomaterials enhance SDT by improving sonosensitizer delivery, tumor accumulation, and overcoming hypoxia, thereby increasing therapeutic efficacy. • The review highlights recent advances in nanosonosensitizers for both monotherapy and synergistic therapy, particularly for orthotopic tumors that are challenging for conventional treatments. • Despite promising preclinical results, the unclear mechanism and suboptimal efficiency of SDT remain barriers to clinical translation, necessitating further research.
Abstract
Sonodynamic therapy (SDT) as an emerging modality for malignant tumors mainly involves in sonosensitizers and low-intensity ultrasound (US), which can safely penetrate the tissue without significant attenuation. SDT not only has the advantages including high precision, non-invasiveness, and minimal side effects, but also overcomes the limitation of low penetration of light to deep tumors. The cytotoxic reactive oxygen species can be produced by the utilization of sonosensitizers combined with US and kill tumor cells. However, the underlying mechanism of SDT has not been elucidated, and its unsatisfactory efficiency retards its further clinical application. Herein, we shed light on the main mechanisms of SDT and the types of sonosensitizers, including organic sonosensitizers and inorganic sonosensitizers. Due to the development of nanotechnology, many novel nanoplatforms are utilized in this arisen field to solve the barriers of sonosensitizers and enable continuous innovation. This review also highlights the potential advantages of nanosonosensitizers and focus on the enhanced efficiency of SDT based on nanosonosensitizers with monotherapy or synergistic therapy for deep tumors that are difficult to reach by traditional treatment, especially orthotopic cancers.
1. Introduction
Nowadays, cancer has become one of the main causes of human death, and the prevalence rate is still on the rise every year [1–4]. Although the existing three major treatments, including surgery, chemotherapy, and radiotherapy, have achieved certain results in the treatment of cancer, serious adverse effects on normal tissues are inevitable for chemotherapy and radiotherapy as well as traumatic for surgery [5, 6]. Thus, it is urgent to develop an effective and precise non-invasive treatment. With the development of science and technology, phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), has developed a lot [7–9]. During PDT and PTT, the core component photosensitizer is excited under light irradiation with a suited wavelength and produces reactive oxygen species (ROS) and heat to kill tumor cells, respectively [10–14]. Phototherapy has a good application prospect owing to the merits of spatiotemporal selectivity, non-invasiveness, non-drug resistance, and less side effects [15–20]. However, because of the poor penetration depth of light, phototherapy is limited to the cure of lesion on the skin or surface [21–23].
In contrast, ultrasound (US) as one kind of mechanical waves has stronger tissue penetration, which is widely applied in the diagnosis of abdominal diseases [24, 25]. In recent years, it has made great progress in the fields of cardiac US, obstetrics and gynecology US, and endovascular US, so it has shown extensive application potential in the detection and treatment of deep-level tumors [26, 27]. In 1989, Umemura et.al found that the combination of US irradiation and hematoporphyrin showed effective antitumor effects in vivo and in vitro, which was attributed to the hematoporphyrin and was activated by US cavitation and generated the cytotoxic ROS [28]. By 1992, Umemura et al. proposed that this treatment was called “sonodynamic therapy” [29, 30]. As an emerging type of non-invasive modality, sonodynamic therapy (SDT) is developed based on PDT, mainly involving low-intensity US and sonosensitizers and having similar principles and function [31, 32]. Compared with other non-invasive treatment such as PDT and PTT, US possesses low tissue attenuation and deep penetration, allowing it to reach tissues up to more than 10 cm in depth [33]. This is significantly greater than the ≈1 cm penetration depth of near-infrared (NIR) light within tissues [34]. Consequently, SDT can address the limitation of traditional phototherapy in treating deep tumors. Furthermore, US is clinically recognized as a safe and effective imaging modality [35]. Hence, SDT holds great promise for clinical applications.
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Mengyao Yang, Xin Wang, Mengke Peng, Fei Wang, Senlin Hou, Ruirui Xing, Aibing Chen (2025). Nanomaterials Enhanced Sonodynamic Therapy for Multiple Tumor Treatment. Nano-Micro Letters. https://doi.org/10.1007/s40820-025-01666-8
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Frequently Asked Questions
What is sonodynamic therapy (SDT)?
Sonodynamic therapy (SDT) is an emerging non-invasive cancer treatment that combines low-intensity ultrasound and sonosensitizers to generate cytotoxic reactive oxygen species (ROS) that kill tumor cells. It offers deep tissue penetration and minimal side effects compared to traditional therapies.
How do nanomaterials enhance sonodynamic therapy?
Nanomaterials enhance SDT by improving the delivery and accumulation of sonosensitizers at tumor sites, overcoming tumor hypoxia, and enabling synergistic therapies. They can be engineered to respond to ultrasound, increasing ROS production and therapeutic efficacy.
What are the main challenges of SDT?
The main challenges of SDT include the unclear underlying mechanism, suboptimal therapeutic efficiency, and limited clinical translation. Additionally, the development of efficient and biocompatible sonosensitizers remains a hurdle.
What types of sonosensitizers are used in SDT?
Sonosensitizers are classified into organic (e.g., porphyrins, phthalocyanines) and inorganic (e.g., titanium dioxide, gold nanoparticles) types. Nanosonosensitizers, which are nanomaterial-based, are being developed to improve solubility, targeting, and ROS generation.
Why is SDT particularly promising for deep tumors?
Ultrasound can penetrate tissues up to 10 cm or more, significantly deeper than light used in phototherapy (about 1 cm). This allows SDT to treat deep-seated tumors, such as orthotopic cancers, that are difficult to reach with conventional non-invasive methods.
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