A cascade nanoreactor for enhancing sonodynamic therapy on colorectal cancer via synergistic ROS augment and autophagy blockage

The ultrasound-triggered sonodynamic therapy (SDT) with high tissue penetration, high spatiotemporal selectivity, and non-invasive advantages represents an emerging approach to eradicating deep-seated solid tumors. However, the outcomes of SDT are typically hampered by the inefficient generation of reactive oxygen species (ROS) and the activation of protective autophagy. Here, to improve the antitumor efficiency of SDT on colorectal cancer, we rationally design a cascade nanoreactor by incorporating sonosensitizer Ce6 and autophagy inhibitor chloroquine into the homologous tumor cell membrane-modified hollow polydopamine nanocarrier that is pre-doped with platinum nanozymes (designated as [email protected]@M). The cascade reactions of [email protected]@M are evidenced by the results that HP exhibits superoxide dismutase-mimicking activity that converts O2·− to O2 and H2O2, and platinum nanozymes further catalyze the excess H2O2 to produce toxic ·OH and O2. [email protected]@M effectively accumulates in the tumor cells, resulting in a remarkably enhanced SDT efficiency for eliminating the tumor cells in vitro and in vivo. Under ultrasound irradiation, [email protected]@M effectively alleviates the hypoxic condition, enhances ROS generation, and inhibits the protective autophagy pathway, which results in stimulating apoptosis and ferroptosis in vitro and in vivo. The RNA-seq analyses also confirmed apoptosis and ferroptosis pathways involved in the [email protected]@M treatment. This cascade nanoreactor will provide a promising strategy for augmenting SDT eradication against tumors by modulation of ROS and autophagy.