Unzippable Siamese Nanoparticles for Programmed Two-Stage Cancer Immunotherapy.

Epigenetic drugs (epi-drugs) can destruct cancer cells and initiate both innate and adaptive immunity, yet they have achieved very limited success in solid tumors so far, partly attributing to their concurrent induction of the myeloid-derived suppressor cell (MDSC) population. Here, we develop dissociable Siamese nanoparticles (SIANPs) for tumor cell-targeted delivery of epi-drug CM-272 and MDSC-targeted delivery of small molecule inhibitor Ibrutinib. The SIANPs are assembled via interparticle DNA annealing and detached via tumor microenvironment-triggered strand separation. Such binary regulation induces endogenous retrovirus expression and immunogenic cell death in tumor cells while restraining the immunosuppressive effects of MDSCs, and synergistically promote dendritic cell maturation and CD8 + T cell activation for tumor inhibition. Significantly, immune microenvironment remodeling via SIANPs further overcomes tumor resistance to immune checkpoint blockade therapy. Our study represents a two-pronged approach for orchestrating immune responses, and pave a new way for employing epi-drugs in cancer immunotherapy. This article is protected by copyright. All rights reserved.