Copper-Consuming Nanoplatform for Alleviating Hypoxia and Overcoming Resistance to Sonodynamic Therapy of Breast Cancer

Sonodynamic therapy (SDT) is a promising treatment modality for breast cancer; however, its effectiveness is often impeded by the hypoxic tumor microenvironment owing to an insufficient oxygen supply in the solid tumors. To overcome this challenge, we elaborately developed a 4T1 tumor-targeted multifunctional nanoagent by integrating both dendrimer-structured copper chelating agents and organic sonosensitizers (IR820) into a biotin-modified nanoliposome via a microfluidic-assisted self-assembly. In particular, the aforementioned copper chelating agent was constructed by introducing multiple xanthate groups into a dendrimer polymer, which showed a significant selectivity for the consumption of the intracellular copper levels. Based on this, the nanoliposome-based therapeutic not only disrupted the activity of the mitochondrial complex IV to directly inhibit the tumor cell proliferation but also suppressed the resistance to the SDT via inhibition of the oxygen consumption for cellular respiration. Both <i>in vitro</i> and <i>in vivo</i> studies confirmed that the designed nanoagents exhibit a synergistic tumor inhibition effect of copper consumption and IR820-mediated SDT. Taken together, this approach establishes a proof-of-concept for the construction of a copper-ion-modulated nanomedicine to significantly enhance the efficiency of oxygen-dependent cancer treatments.