Multifunctional porous organic polymer-based hybrid nanoparticles for sonodynamically enhanced cuproptosis and synergistic tumor therapy

Cuproptosis has gained significant attention among different cell death pathways in cancer therapy, which relies on the excessive accumulation of Cu 2+ in mitochondria of tumor cells. Nevertheless, the high levels of glutathione in tumor microenvironment chelates with Cu 2+ and thereby reducing its cytotoxicity. In this study, we designed core-shell porous organic polymers (POPs) nanoparticles to deliver and accumulate Cu 2+ in tumor cells for enhanced cuproptosis. The porous organic polymers, containing bipyridine structural units, were synthesized on the aminated silica template, followed by the coordination of Cu 2+ and the loading of artesunate (ART) as the sonosensitizer, yielding the Cu/ART@Hpy nanoparticles. In the acidic tumor microenvironment, the nanoparticles realized pH-responsive release of Cu 2+ . Meanwhile, the generation of ROS under ultrasound irradiation depleted intracellular glutathione, leading to the increased intracellular accumulation of Cu 2+ for cuproptosis and triggering multiple cell death mechanisms for sonodynamically enhanced tumor therapy. Our study highlights the potential of the porous organic polymer as a platform for cuproptosis and synergistic tumor therapy. Statement of Significance Cuproptosis is induced by the excessive accumulation of Cu²⁺ within the mitochondria of tumor cells. However, the high level of glutathione in the tumor microenvironment can chelate Cu²⁺, thereby reducing the therapeutic efficacy. In this study, we developed the core-shell structured Cu/ART@Hpy nanoparticles for pH-responsive delivery of Cu²⁺. Under ultrasound irradiation, the generated reactive oxygen species deplete intracellular glutathione, enhancing Cu²⁺ accumulation for cuproptosis and activating multiple cell death pathways. The Cu/ART@Hpy nanoparticles enable sonodynamically enhanced cuproptosis, achieving synergistic tumor therapy.