Human iPS Cells Loaded with MnO(2)-Based Nanoprobes for Photodynamic and Simultaneous Enhanced Immunotherapy Against Cancer

HIGHLIGHTS: MnO(2)@Ce6 nanoprobes-loaded-iPS cells (iPS-MnO(2)@Ce6) were developed for enhanced photodynamic and immunotherapy against cancer. Under the guidance of multi-mode real-time imaging, iPS-MnO(2)@Ce6 achieved an enhanced photodynamic therapeutic effect and stimulated a strong anti-tumor immune response in the tumor-bearing mouse. ABSTRACT: How to trigger strong anti-tumor immune responses has become a focus for tumor therapy. Here, we report the human-induced pluripotent stem cells (iPSs) to deliver MnO(2)@Ce6 nanoprobes into tumors for simultaneous photodynamic therapy (PDT) and enhanced immunotherapy. Ce6 photosensitizer was attached on manganese dioxide (MnO(2)) nanoparticles, and resultant MnO(2)@Ce6 nanoprobes were delivered into mitomycin-treated iPSs to form iPS-MnO(2)@Ce6 nanoprobes. The iPS-MnO(2)@Ce6 actively targeted in vivo tumors, the acidic microenvironment triggered interaction between MnO(2) and H(2)O(2), released large quantities of oxygen, alleviated hypoxia in tumor. Upon PDT, singlet oxygen formed, broken iPSs released tumor-shared antigens, which evoked an intensive innate and adaptive immune response against the tumor, improving dendritic cells matured, effector T cells, and natural killer cells were activated. Meanwhile, regulatory T cells were reduced, and then the immune response induced by iPS-MnO(2)@Ce6 was markedly stronger than the immune reaction induced by MnO(2)@Ce6 (P < 0.05). The iPS-MnO(2)@Ce6 markedly inhibited tumor growth and metastasis and reduced mortality in mice models with tumor. Human iPSs loaded with MnO(2)-based nanoprobes are a promising strategy for simultaneous PDT and enhanced immunotherapy against tumor and own clinical translational prospect. [Image: see text] ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40820-020-00452-y) contains supplementary material, which is available to authorized users.