Hollow Nanoporous Prussian Blue Nanocubes Enriched with Cu²⁺ and Loaded with Quercetin for Synergistic Tumor Therapy

Combination therapy based on Prussian blue nanoparticles (PB NPs) is particularly effective in cancer because of their outstanding photothermal properties and excellent biocompatibility. However, the application of PB in tumor therapy is hindered by their poor reactive oxygen species (ROS) production capacity, and low drug loading rate. More importantly, PB NPs could activate heat shock proteins (HSPs) in photothermal therapy, which induces the self-protection of tumor cells. Structural and functional modulation improved antitumor efficacy by enhancing reactive oxygen species (ROS) production and inhibiting heat shock protein expression. In this work, we synthesized Cu 2+ -enriched hollow nanoporous PB nanocubes (Cu-HNPB NCs) that enhanced the •OH generating capability of PB as Cu hybridization increases the oxidation potential of PB. Moreover, in the tumor milieu, Cu 2+ release depletes glutathione (GSH) and converts to Cu +, further improving ROS levels. Excess ROS amplifies cellular oxidative stress and destroys the heat-induced formation of HSPs, thus breaking the self-protection mechanism of tumor cells. To enhance the therapeutic efficiency, quercetin (QUE) was loaded in Cu-HNPB NCs (Cu-HNPB@QUE NCs). Surprisingly, the large specific surface area (127.79 m 2 g –1 ) endowed Cu-HNPB NCs with ultrahigh loading capacity (57.25%). As the nanoplatform enhances synergistic therapeutic effects, this study provides a new approach for designing multimodal combination nanomedicine.