# Exosome-Enhanced Sonodynamic Therapy in Cancer: Emerging Synergies and Modulation of the Tumor Microenvironment

## TL;DR

This review explores using exosomes to improve sonodynamic therapy for cancer, enhancing drug delivery and tumor targeting while reducing side effects.

## Contribution

The paper introduces a comprehensive overview of using exosomes to enhance sonodynamic therapy, focusing on tumor targeting and microenvironment modulation.

## Key findings

- Exosomes improve the stability and tumor targeting of sonosensitizers in sonodynamic therapy.
- Combining exosomes with SDT can stimulate immune responses and reshape the tumor microenvironment.
- EV-based SDT shows potential for clinical translation with reduced side effects and improved therapeutic precision.

## Abstract

Standard cancer treatments often cause severe side effects and struggle to reach deep-seated tumors, creating an urgent need for safer, more precise therapies. Sonodynamic therapy (SDT) has emerged as a promising non-invasive approach that uses harmless sound waves to activate special drugs capable of killing cancer cells. However, achieving effective delivery and accumulation of these drugs within tumors remains challenging. This review explores an innovative strategy that employs tiny particles released by cells, called extracellular vesicles (EVs), as smart carriers to deliver these drugs directly to tumors. Since EVs are naturally produced by the body, they are well-tolerated and can be engineered to enhance drug stability and tumor targeting. By combining SDT with EV-based drug delivery, it may be possible not only to destroy cancer cells more precisely, but also to stimulate the immune system to fight the disease, paving the way for safer and more effective cancer therapies.

The development of safer, more effective, and tumor-specific therapeutic strategies remains a major challenge in oncology. Conventional treatments such as chemotherapy and radiotherapy often cause severe side effects and are limited in their ability to target deep-seated or resistant tumors. In this context, sonodynamic therapy (SDT) has emerged as a promising, non-invasive option, harnessing low-intensity ultrasound to activate sonosensitizers deep within tissues and generate cytotoxic reactive oxygen species (ROS) that selectively induce cancer cell death. Interestingly, SDT can also be combined with other therapies to achieve synergistic effects. However, despite encouraging preclinical results, SDT clinical translation is hindered by the poor aqueous solubility, instability, and low tumor specificity of traditional sonosensitizers. To overcome these limitations, recent studies have focused on employing extracellular vesicles (EVs), especially exosomes, as natural, biomimetic nanocarriers for sonosensitizer delivery. EVs offer unique advantages, including high biocompatibility, low immunogenicity, and intrinsic tumor-targeting ability, which make them ideal platforms for improving the therapeutic precision of SDT. Although several delivery strategies have been proposed, a comprehensive and focused overview of approaches specifically designed to enhance SDT performance using EVs is currently lacking. This review summarizes recent advances in integrating EVs with SDT for cancer treatment. It discusses the mechanisms underlying SDT, the engineering strategies developed to enhance exosome functionality, and the synergistic effects achieved through this combination. Furthermore, this review emphasizes that EV-based SDT not only enhances tumor accumulation of the therapeutic nanoplatforms, but also actively remodels the tumor microenvironment by improving oxygen availability, reversing immunosuppressive conditions, and triggering durable antitumor responses. Finally, the review addresses the translational challenges and outlines the critical future directions required to advance this promising therapeutic approach toward clinical application.