Au@MnSe Core-Shell Nanoagent Enabling Immediate Generation of Hydroxyl Radicals and Simultaneous Glutathione Deletion Free of Pre-Reaction for Chemodynamic-Photothermo-Photocatalytic Therapy with Significant Immune Response.

As a typical tumor microenvironment-responsive therapy, chemodynamic therapy (CDT), producing hydroxyl radicals ( OH) to eliminate tumor cells, has demonstrated great promise. Nevertheless, there are still major challenges: OH generated from endogenous H O is usually insufficient; the CDT effect is strongly dependent on the pre-reaction with glutathione. Addressing the challenges, Au@MnSe core-shell nanoagent for synergetic chemodynamic-photothermo-photocatalytic therapy combined with tetramodal imaging, including magnetic resonance imaging, computed tomography, photoacoustic, and infrared thermal imaging is reported. Distinct from the reported glutathione-depleting agents, Mn in MnSe allows immediate generation of OH, independent of pre-reaction. Meanwhile, Mn consumes glutathione by its conversion to Mn . The Au-MnSe combination promotes photothermal conversion and photocatalytic reaction, resulting in largely enhanced OH generation from endogenous H O and significant hyperthermia. Meanwhile, immune response is effectively activated: the intratumoral expression of programmed cell death-1 and proinflammatory cytokines increase to 4-7 folds; the cytotoxic and helper T lymphocytes cells in the tumor area increase to more than 2.5-folds; an evident, temporary systemic immunostimulatory effect is demonstrated. High tumor inhibition rate (≈97.3%) and greatly prolonged survival are obtained. This highly-integrated design coordinating three different therapies with four different imaging modals provide new possibilities for high-performance theranostic nanoagents.