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, dissociable Siamese nanoparticles (SIANPs) are developed 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 promotes 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. This study represents a two‐pronged approach for orchestrating immune responses, and paves a new way for employing epi‐drugs in cancer immunotherapy. Detachable Siamese nanoparticles (SIANPs) are programmed to separate in responding to abundant extracellular adenosine triphosphate in the tumor microenvironment, conferring two‐pronged delivery of epigenetic drugs and immune modulators to tumor cells and myeloid‐derived suppressor cells (MDSCs), respectively. SIANP treatment prevents MDSC induction driven by epigenetic drugs, enabling epigenetic therapy in solid tumors such as breast and colorectal cancers.