Intelligent MnO₂/Cu2–xS for Multimode Imaging Diagnostic and Advanced Single-Laser Irradiated Photothermal/Photodynamic Therapy

Lately, photothermal therapy (PTT) and photodynamic therapy (PDT) dual-modal therapy has attracted much attention in cancer therapy as a synergistic therapeutic model. However, the integration of PDT and PTT in a single nanoagent for cancer therapy is still a challenging task. Herein, an intelligent MnO₂/Cu2- xS-siRNA nanoagent simultaneously overcoming inherent limitations of PDT and PTT with remarkable PTT&PDT therapeutic efficiency enabling a multimode accurate tumor imaging diagnostic is designed. We first develop a general method to decorate Cu2- xS on the surface of MnO₂ nanosheet (MnO₂/Cu2- xS); then, it is loaded with heat shock protein (HSP) 70 siRNA to obtain MnO₂/Cu2- xS-siRNA. The intracellular microRNA (miRNA) imaging can be realized by loading miRNA detection probes. In the tumor acidic microenvironment, the MnO₂ is reduced to Mn²⁺ ion and triggers the decomposition of H₂O₂ into O₂ to relieve tumor hypoxia. The reduced Mn²⁺ ions significantly enhance magnetic resonance imaging (MRI) contrast, and the Cu2- xS acts as a powerful photoacoustic (PA) and photothermal (PT) imaging agent, leading to trimodal accurate tumor-specific imaging and detection. Under a single NIR laser irradiation, the nanosystem exhibits superiority of PTT&PDT efficiency owing to siRNA-mediated blocked heat-shock response and MnO₂-related relieved tumor hypoxia. This work highlights the great promise of modulating the tumor cellular defense mechanism and microenvironment with intelligent multifunctional nanoagents to achieve a comprehensive fighting cancer effect.