(C-92) Stimuli-responsive extracellular vesicles for safe and targeted sonodynamic cancer therapy

Introduction:: Sonodynamic therapy has emerged as a potential alternative to conventional photodynamic therapy due to its ability to effectively treat deep-seated tumors. However, safe and efficient delivery of sonosensitizers to target tumor cells remains a significant challenge. Extracellualr vesicles (EVs) are cell-derived nanocarriers and have been widely employed as biocompatible drug carriers. In this study, engineered EVs that can facilitate the release of anticancer drugs in response to specific stimuli in tumors were developed for enhanced anticancer efficacy while avoiding unwanted drug release in surrounding normal tissues.


Materials and Methods:: Indocyanine green (ICG), which functions as both a sonosensitizer and photoacoustic (PA) imaging agent, was loaded into EVs, together with paclitaxel (PTX) and sodium bicarbonate (SBC), to achieve pH-responsive chemo-sonodynamic combination therapy. The intracellular ROS production and viability of MCF-7 cells incubated with ICG-loaded EVs were quantified before and after ultrasound (US) irradiation.


Results, Conclusions, and Discussions:: The EVs significantly improved the cellular uptake of ICG, thus triggering enhanced sonodynamic effects in breast cancer cells. SBC-, ICG-, and PTX-loaded EV [SBC-EV(ICG/PTX)] efficiently released the PTX in response to acidic pH in the endo/lysosomes because CO₂ bubbles generated from the SBC caused the EV membranes to burst. The drug release was further facilitated by US treatment, demonstrating dual pH/US-responsive drug release. The ICG- and PTX-loaded EVs exhibited efficient anticancer activity against breast tumor cells owing to the combination of chemo-sonodynamic therapy. Notably, a single intravenous injection of ICG- and PTX-loaded EVs with US irradiation significantly suppressed tumor growth in mice without systemic toxicity.

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