Hyaluronic acid-modified nanoparticles for chemo/sonodynamic therapy: Maximizing antitumor efficacy through the induction of ferroptosis and apoptosis

GSH-responsive HPCT enable CT/SDT synergistic therapy. • HPCT induces both ferroptosis and apoptosis. • HPCT actively target CD44-overexpressing tumor cells. • Dual death pathways overcome single-treatment limitations for enhanced efficacy. Cancer is one of the leading causes of death worldwide. Chemotherapy (CT) is one of the main clinical treatment modalities; however, it has limitations as a single treatment approach. To achieve a multi-modal synergistic therapy, this study designed and synthesized two amphiphilic molecules, PEG-SS-CPT and HA-SS-Ce6, and subsequently constructed intelligent nanoparticles HPCT through self-assembly, which possess both active targeting and glutathione (GSH) responsiveness for CT and sonodynamic therapy (SDT). This system employs hyaluronic acid (HA) to specifically target tumor cells that exhibit elevated CD44 expression. It responds to the high levels of GSH present in the tumor microenvironment, allowing for the release of CT drug camptothecin (CPT), while also producing singlet oxygen through Ce6 activation under ultrasound (US) stimulation, thereby simultaneously inducing apoptosis and ferroptosis in tumor cells. In the CT26 colon cancer-bearing mouse model, HPCT combined with US demonstrated a significant synergistic anti-tumor effect, with a tumor growth inhibition rate of 80.4 ± 3.1%, and did not cause significant systemic toxicity. This study indicates that through the rational design of intelligent nanoparticles integrating CT and SDT, it is possible to effectively overcome the limitations of single treatment modalities, providing a new strategy to enhance cancer treatment efficacy.