A versatile nanoplatform for enhanced sonodynamic therapy <i>via</i> hypoxia alleviation, glutathione depletion, and calcium overload

Ultrasound (US) offers exceptional tissue penetration, making it a promising modality for the treatment of deep-seated cancers. Sonodynamic therapy (SDT) leverages US to activate low-toxicity sonosensitizers, generating cytotoxic reactive oxygen species (ROS) that induce cancer cell death. However, its clinical effectiveness is hindered by challenges such as hypoxia and overexpression of glutathione (GSH) in the tumor microenvironment (TME). In this study, we designed and synthesized a sodium-hyaluronate-modified TCCP-BSO@CaO₂@SH nanoplatform (TBC@SH NPs) to enhance SDT efficacy in hepatocellular carcinoma (HCC). The TBC@SH NPs were prepared through a straightforward one-pot method, involving the self-assembly of CaO₂ nanoparticles with tetrakis (4-carboxyphenyl) porphyrin (TCPP) and L-buthionine sulfoximine (BSO), followed by surface modification with sodium hyaluronate (SH) for targeted delivery to CD44 receptors on HCC cells. In the mildly acidic TME, TBC@SH NPs facilitate oxygen release, induce calcium ion overload, inhibit GSH synthesis, and generate substantial reactive oxygen species (ROS) under ultrasound irradiation. These synergistic effects collectively amplify oxidative stress, significantly enhancing SDT therapeutic efficacy in HCC treatment. Encouraging results were observed in both <i>in vitro</i> HCC cell models and <i>in vivo</i> animal tumor models. This study highlights the potential of ultrasound-mediated SDT therapy for HCC and provides valuable insights into the development of integrated nanoplatforms for enhanced HCC treatment.