A nucleic acid nanogel dually bears siRNA and CpG motifs for synergistic tumor immunotherapy

Abstract

The immune system plays a key role in restraining tumor progression. Therefore, enhancing immune functions using immune stimulants, such as unmethylated CpG oligonucleotides, has emerged as a promising strategy for antitumor therapy. However, poor cellular uptake of negatively charged oligonucleotides and M2 polarization of tumor-associated macrophages remain two major challenges for CpG-based immunotherapy. Herein, we construct a spherical nucleic acid (SNA)-like nanogel assembled by a CpG-grafted polycaprolactone (CpG-g-PCL) brush and an anti-STAT3 siRNA crosslinker for synergistic tumor immunotherapy. After accumulation at the tumor site, this dual siRNA- and CpG-bearing nanogel (CpGgel-siSTAT3) can efficiently trigger M1 type macrophage activation and deter its M2 polarization via block STAT3 signaling, increase the intratumor CD8⁺ T cell infiltration, and thus successfully restrain tumor growth. Our study demonstrates the new potential of a nucleic acid nanogel platform for the co-delivery of different therapeutic oligonucleotides and combinatorial CpG-based immunotherapy.