Cyclic brush spherical nucleic acids for enhanced gene-immunotherapy of hepatocellular carcinoma via neutrophil polarization

The use of liver-specific endogenous microRNA-122 (miR-122) for efficient gene therapy of hepatocellular carcinoma (HCC) remains a significant challenge due to the severe immunosuppressive microenvironment of HCC. We report herein the construction of a miR-122-based cyclic brush spherical nucleic acid (SNA) nanoplatform for highly efficient gene therapy of HCC. Specifically, free miR-122 chains were conjugated to an optimized cyclic poly(2-hydroxyethyl methacrylate) (c-P(HEMA)) core via click chemistry, affording cyclic brush miR-122 (cb-P(HEMA-miR-122)), which can further self-assemble into stabilized SNAs with an ultra-small average hydrodynamic diameter of 105.8 nm. The resulting cb-P(HEMA-miR-122) SNAs can circumvent the immunosuppressive microenvironment of HCC and promote neutrophil polarization for activating the antitumor immunity, leading to a high tumor inhibition rate (TIR) of 87.4% in a Hepa1-6 mice HCC model. This study highlights the mere use of a cyclic topology for SNA construction as a robust yet simple strategy for enhanced gene-immunotherapy of HCC.