Stimulus-Responsive Copper Complex Nanoparticles Induce Cuproptosis for Augmented Cancer Immunotherapy

Cuproptosis, an emerging form of programmed cell death, has received tremendous attention in cancer therapy. However, the efficacy of cuproptosis remains limited by the poor delivery efficiency of copper ion carriers. Herein, copper complex nanoparticles (denoted as Cu(I) NP) are developed that can efficiently deliver copper complex into cancer cells to induce cuproptosis. Cu(I) NP demonstrate stimulus-responsive release of copper complexes, which results in mitochondrial dysfunction and promotes the aggregation of lipoylated dihydrolipoamide S-acetyltransferase (DLAT), leading to cuproptosis. Notably, Cu(I) NP not only induce cuproptosis, but also elicit robust immune responses to suppress tumor growth. Overall, this study provides a promising strategy for cuproptosis-based cancer therapy. Cu(I) can self-assemble with ROS-sensitive polymer to form Cu(I) NP via electrostatic and hydrophilic interaction. Upon intravenous administration, Cu(I) NP selectively accumulate at tumor sites to release Cu(I). Notably, the released Cu(I) effectively induced cuproptosis to trigger immunogenic cell death (ICD) at the tumor site, thereby augmenting the anti-tumor immune response. image