Two-Dimensional MXene-Originated <i>In Situ</i> Nanosonosensitizer Generation for Augmented and Synergistic Sonodynamic Tumor Nanotherapy

Abstract

Despite the merits of high tissue-penetrating depth, no ionizing radiation, and low cost, sonodynamic therapy (SDT) still suffers from a low quantum yield of reactive oxygen species (ROS), limited delivery efficiency, and potential toxicity of sonosensitizers. Different from the direct delivery of sonosensitizers into tumor tissue for SDT, this work reports the fabrication of two-dimensional (2D) nanosonosensitizers/nanocatalysts (Ti₃C₂/CuO₂@BSA) for the <i>in situ</i> generation of nanosonosensitizers by responding to the tumor microenvironment, achieving the high-performance and synergistic sonodynamic/chemodynamic tumor therapy. CuO₂ nanoparticle integration on 2D Ti₃C₂ MXene achieved <i>in situ</i> H₂O₂ generation in an acidic tumor microenvironment for oxidizing Ti₃C₂ to produce TiO₂ nanosonosensitizers, accompanied by the enhanced separation of electrons (e^-) and holes (h⁺) by the carbon matrix after oxidation, further augmenting the SDT efficacy. Ultrasound irradiation during the sonodynamic process also enhanced the Cu-initiated Fenton-like reaction to produce more ROS for synergizing the sonodynamic tumor therapy. The experimental results confirm and demonstrate the synergistic therapeutic effects of chemodynamic and sonodynamic nanotherapy both <i>in vitro</i> and <i>in vivo</i>. The antitumor mechanisms of synergistic chemodynamic and sonodynamic therapies are associated with the upregulation of oxidative phosphorylation, ROS generation, and apoptosis as demonstrated by RNA sequencing. This work thus provides a distinct paradigm of 2D MXene-originated <i>in situ</i> nanosonosensitizer generation for augmented and synergistic sonodynamic tumor nanotherapy.