One Responsive Stone, Three Birds: Mn(III)‐Hemoporfin Frameworks with Glutathione‐Enhanced Degradation, MRI, and Sonodynamic Therapy

Abstract Ultrasound‐driven sonodynamic therapy (SDT) catches numerous attentions for destroying deep‐seated tumors, but its applications suffer from unsatisfactory therapeutic effects and metabolism. Furthermore, SDT is usually weakened by the complex tumor microenvironment, such as the overexpression of glutathione (GSH). To address these issues, Mn(III)‐hemoporfin frameworks (Mn(III)‐HFs) are reported as nanosonosensitizers by using biocompatible hematoporphyrin monomethyl‐ether (HMME) to coordinate with Mn(III) ions. Mn(III)‐HFs/PEG can react with GSH to produce Mn(II) ions and oxidized glutathione (GSSG), resulting in three fascinating features: 1) the redox reaction facilitates the decomposition of Mn(III)‐HFs/PEG and then collapse of nanostructures, improving the biodegradability; 2) Mn(II) ions with five unpaired 3d‐electrons exhibit better magnetic resonance imaging (MRI) ability compared to Mn(III) ions with four electrons; 3) both the depletion of endogenous GSH and the dissociated HMME boost 1 O 2 generation ability under US irradiation. As a result, when Mn(III)‐HFs/PEG dispersion is intravenously administered into mice, it exhibits high‐contrast T 1 / T 2 dual‐modal MRI and significant suppression for the growth rate of the deep‐seated tumor. Furthermore, Mn(III)‐HFs/PEG can be efficiently metabolized from the mice. Therefore, Mn(III)‐HFs/PEG exhibit GSH‐enhanced degradation, MRI, and SDT effects, which provide some insights on the developments of other responsive nanosonosensitizers.