Cu-deficient Cu–Fe Prussian blue analogues enable phosphate/GSH-coupled redox remodeling for catalytic/sonodynamic cancer therapy

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Cu–Fe Prussian blue analogues (PBAs) are promising platforms for nanocatalytic medicine owing to their redox-active Cu/Fe centers and open metal–cyano coordination frameworks. Nevertheless, the influence of Cu deficiency on their enzyme-mimetic catalytic behavior in tumor-relevant environments containing phosphate and glutathione (GSH) remains poorly defined. Here, we constructed a Cu-deficient Cu–Fe PBA core (CuPBA-D), loaded it with hematoporphyrin monomethyl ether (HMME), and coated it with hyaluronic acid (HA) to yield CuPBA-D/HMME/HA for microenvironment-responsive catalytic/sonodynamic cancer therapy. Etching-induced Cu deficiency altered the local Cu/Fe electronic environment, strengthened H 2 O 2 adsorption and activation, and enhanced catalytic activity, as supported by experimental results and density functional theory (DFT) calculations. CuPBA-D displayed pH-dependent H 2 O 2 conversion, with O 2 •− generation favored under mildly acidic conditions and O 2 evolution becoming more prominent near neutrality. Phosphate-containing media also increased the surface fractions of higher-valence Cu/Fe species and accelerated CuPBA-D-mediated GSH consumption, supporting phosphate-facilitated interfacial redox remodeling. In addition, CuPBA-D underwent GSH-concentration-dependent framework disassembly when phosphate and GSH coexisted, indicating coupled interfacial redox and structural evolution. The CAT-like O 2 -generating activity of CuPBA-D increased oxygen availability for HMME-mediated 1 O 2 production during ultrasound irradiation, thereby strengthening the sonodynamic response. In vitro, CuPBA-D/HMME/HA plus ultrasound increased intracellular ROS accumulation and induced ferroptosis-associated damage, supported by biochemical, ultrastructural, and transcriptomic analyses. In a 4T1 breast tumor model, the combined treatment markedly suppressed tumor growth while showing favorable biosafety under the tested conditions. Collectively, these findings identify phosphate/GSH-coupled redox remodeling in Cu-deficient Cu–Fe PBAs and provide a design basis for tumor-microenvironment-responsive nanoplatforms integrating catalytic ROS generation, redox disruption, and O 2 -assisted sonodynamic therapy.

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