Redirecting natural killer cells to potentiate adoptive immunotherapy in solid tumors through stabilized Y-type bispecific aptamer.

Modulating interactions between immune effector cells and tumor cells in vivo using a bispecific aptamer (Ap) is a promising strategy for cancer immunotherapy. However, it remains a technical challenge owing to the complex and dynamic internal environment accompanied by severe degradation. Herein, by using a Y-shaped DNA scaffold, a bispecific and stabilized Y-type Ap is designed to redirect natural killer (NK) cells to enhance adoptive immunotherapy of hepatocellular carcinoma (HCC) solid tumors. Y-type Ap is constituted by the HCC-specific Ap TLS11a linked with the CD16-specific Ap through a Y-shaped DNA scaffold. Owing to the rigid structure, Y-type Ap shows high stability in 10% serum for over 72 h and resistance to denaturation by 8 M urea. Additionally, the Y-type Ap exhibits more potent avidity to bind with NK cells and tumor cells both in vitro and in vivo, resulting in higher cytokine secretion and excellent antitumor efficiency. Collectively, this study offers a translational platform for constructing stable bispecific Ap, offering considerable potential to enhance adoptive immunotherapy of solid tumors.