Combination of Metal‐Phenolic Network‐Based Immunoactive Nanoparticles and Bipolar Irreversible Electroporation for Effective Cancer Immunotherapy

Abstract To circumvent the limitations of conventional cancer immunotherapy, it is critical to prime antigen‐presenting cells (APCs) to initiate the cancer‐immune cycle. Here, the authors develop a metal‐phenolic network (MPN)‐based immunoactive nanoparticle in combination with irreversible electroporation (IRE) for an effective cancer immunotherapy. The MPN nanoparticles are synthesized by coordinating tannic acid with manganese (Mn) ions, and subsequent coating with CpG‐oligodeoxynucleotides (CpG‐ODNs) via hydrogen bonding. The CpG‐ODN‐coated Mn‐phenolic network (CMP) nanoparticles are effectively internalized into macrophages, a type of APCs, and successfully trigger M1 polarization to promote release of proinflammatory cytokines. Notably, the CMP nanoparticles demonstrate an extended retention time period than the free CpG‐ODN in the tumor. The tumor microenvironment tailored bipolar IRE, enhances the therapeutic efficacy by significantly broadening the ablation zone, which further increases immunogenic cell death (ICD). Ultimately, the simultaneous CMP nanoparticles and IRE treatment successfully inhibit tumor growth and prolong survival in a mouse tumor model. Thus, CMP nanoparticles are empowered with Mn and CpG‐ODN immunomodulators and the tumor microenvironment tailored bipolar IRE will be a new tool for effective cancer immunotherapy to treat intractable malignancies.