MSNs-loaded HMME and Erastin-mediated ferroptosis combined with sonodynamic therapy for HCC treatment.

Background: Ferroptosis can have a major impact on the development and advancement of hepatocellular carcinoma (HCC) due to its clear association with heightened vulnerability to the disease. This study aimed to develop a novel nanoplatform to evaluate its effectiveness in in vivo and in vitro models of HCC.

Methods: Erastin, a compound that induces iron-dependent cell death, and HMME, a sonosensitizer, were enclosed within mesoporous silica nanoparticles (MSNs). The nanoparticles were engineered to exhibit a responsive assembly-disassembly mechanism. Hydrophilic hyaluronic acid (HA) was utilized for conjugation modification to synthesize Erastin/HMME@MSNs-HA. In vivo and in vitro experiments were conducted to elucidate the antitumor mechanisms of this nanomaterial.

Results: In the in vitro cellular experiments, Erastin/HMME@MSNs-HA was rapidly degraded by hyaluronidase, leading to increased endocytosis of the cancer cells. Cellular breakdown led to the generation of harmful reactive oxygen species (ROS), decreased glutathione levels, and increased lipid peroxidation, resulting in a decrease in mitochondrial membrane potential, dysfunctional mitochondria, reduced cell growth, and increased cell death. Additionally, the Erastin/HMME@MSNs-HA nanotherapy platform, when combined with ultrasound (US) treatment, exhibited significant therapeutic effectiveness against tumors in vivo. It induced significant cell death in cancerous tissues, decreased tumor growth, worsened tissue oxygen deprivation, and exhibited good compatibility with the body.

Conclusion: These findings indicate that the nanoplatform can effectively alleviate tumor hypoxia while inducing apoptosis and ferroptosis, laying the foundation for enhancing the efficacy of ROS-mediated HCC therapy.