Carrier-free self-assembled nanodrug with responsive release of carbon monoxide and antisense oligonucleotide for synergistic tumor therapy

Carbon monoxide (CO) is a gaseous signaling molecule, which can induce mitochondrial dysfunction and tumor cell apoptosis by increasing reactive oxygen species (ROS), making it an attractive therapeutic agent for tumors. However, achieving the optimal therapeutic dose of CO is often difficult due to the limited drug loading capacity of delivery systems. Moreover, the CO therapeutic effect is compromised by the overexpression of glutathione (GSH) in tumor cells. Here, we report a nanodrug constructed by self-assembly of CO-releasing molecule Mn(CO) 5 Br and Cy5-modified cystine transporter antisense oligonucleotides. This nanodrug dissociates and releases CO and antisense oligonucleotide in response to overexpressed H 2 O 2 in tumor microenvironment, resulting in the increase of ROS and the decrease of GSH respectively, thus synergistically inducing tumor cell apoptosis. The self-assembled nanodrug shows satisfactory therapeutic effect of inhibiting tumor growth in tumor cells and animal models, and provide a promising strategy for multifunctional anti-tumor synergistic therapy.