Reconstructed adoptive-macrophages with DNA-tetrahedron-CpG/siRNA for synergistic solid tumor immunotherapy

Abstract

Therapeutic nucleic acid delivery to solid tumors remains a challenge due to enzymatic degradation in cellular uptake and endosomal escape process as well as limited cell permeability. Herein, we reconstructed adoptive-macrophages by integrating functional DNA nanostructure-loaded nucleic acid drugs for tumor immunotherapy. The combination of functional small interfering RNAs (siRNAs) and CpG into DNA tetrahedron (DNA-tet) could induce the repolarization of M2 phenotype macrophages to antitumor M1 type, and releasing proinflammatory cytokines to kill tumor cells. The DNA tet-CpG/siRNA-loaded macrophages show excellent cellular uptake efficiency, parallel delivery capability and induce evident apoptosis and necrosis for tumor cells in vitro. In 4T1 xenograft tumor-bearing mice models, the adoptive macrophage with DNA tet-CpG/siRNA could effectively suppress the growth of subcutaneous tumors persistently and have low side effect for major organs. In summary, our proposed combination therapy of immunological macrophage and DNA-tet-CpG/siRNA will supply new ideas for solid tumor therapy.