HMCuS@MnO2 Nanocomplex Responsive to Multiple Tumor Environmental Clues for Photoacoustic/Fluoresence/Magnetic Resonance Trimodal Imaging-Guided and Enhanced Photothermal/Photodynamic Therapy

Hollow mesoporous copper sulfide nanoparticles (HMCuS NPs) are advantagenous in loading small-molecule therapeutic drugs coupled with photothermal ablation for synergistic tumor therapy. However, treatement efficacy mediated by HMCuS NPs is not always satisfactory owing to their insensitivity toward tumor microenvironement (TME), and unpredictable drug leakage may also result in deleterious systemic toxicity. Here, a novel HMCuS@MnO2-based core-shell nanoplatform was developed as a highly efficient TME modulator, which could alleviate tumor hypoxia, deplete the level of intracellular glutathione (GSH) and trigger the dissolution Mn2+. Moreover, MnO2, in situ grown on the surface of HMCuS, may act as the gatekeeper by forming the stimulus-responsive plug within the mesoporous structure, which effectively prevented the pre-matured release of encapsulated photosensitizer chlorin e6 (Ce6) and was responsive to acidic TME for demand-based drug release. Under the condition of 660/808 nm dual-wavelength laser irradiation, hyperthermia-mediated photothermal therapy (PTT) and reactive oxygen species (ROS)-mediated photodynamic therapy (PDT) can be triggered for tumor eradication, which were further enhanced upon the modification of TME. In the meanwhile, splendid photoacoustic(PA)/fluoresence(FL)/magnetic resonance(MR) imaging propery of HMCuS@MnO2/Ce6 (CMC) NPs could enable the realization of more precise, reliable and on-demand combination therapy. In a word, this study illustrated a promising approach to strengthen the efficacy of HMCuS-based nanotherapeutics, which would definitely promote the further exploitation of smarter nanoplatforms for synergistic disease management.