Au@MnSe2 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 2 O 2 is usually insufficient; the CDT effect is strongly dependent on the pre-reaction with glutathione. Addressing the challenges, Au@MnSe 2 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 2+ in MnSe 2 allows immediate generation of • OH, independent of pre-reaction. Meanwhile, Mn 3+ consumes glutathione by its conversion to Mn 2+ . The Au-MnSe 2 combination promotes photothermal conversion and photocatalytic reaction, resulting in largely enhanced • OH generation from endogenous H 2 O 2 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.