Ultrasound cascade regulation of nano-oxygen hybrids triggering ferroptosis augmented sonodynamic anticancer therapy

Sonodynamic therapy (SDT) has attracted great interest in the field of cancer therapy because of its non-invasiveness, deep penetration, and spatiotemporal controllability. However, the sonodynamic effect is severely hindered by hypoxia and a high glutathione (GSH) level in tumor microenvironment. In this work, a new type of nanohybrid sonosensitizer is designed, which incorporates several prominent advantages of organic, inorganic, and natural sonosensitizers for imaging-guided SDT and ferroptosis induction. As an endogenous transporter, hemoglobin (Hb) has dual functions of oxygen and iron supplement. Apparently, Hb can transport iron to the tumor site for Fe-dependent ferroptosis, yet this oxygen carrier is able to enhance the sensitivity of tumor cells to oxygen-driven SDT. We innovatively hybridized Hb, sinoporphyrin sodium (DVDMS), and titanium dioxide (TiO₂) to prepare an integrated nano-oxygen carrier (designated as HDT) for multifarious cancer theranostics, which not only attained satisfactory sonosensitization of DVDMS/TiO₂ but also achieved oxygen-boosted SDT and potent ferroptosis via Hb. Under ultrasound irradiation, the oxygenation of HDT markedly amplified the generation of reactive oxygen species (ROS) in hypoxic tumors, promoted the valence transition of Hb to accelerate Fenton reaction, and led to ferroptosis. This strategy virtually eradicated tumors in situ and exhibited immunoregulatory potential for augmenting anti-tumor effects in vivo and in vitro through ROS formation, O₂ self-supplement, GSH depletion, and lipid peroxidation. Collectively, HDT demonstrated excellent dual-modal imaging performance, providing a valuable platform for photoacoustic/fluorescence-guided SDT and ferroptosis induction in tumor cells.