Self-assembled tetrahedral framework nucleic acid mediates tumor-associated macrophage reprogramming and restores antitumor immunity

Husun Qian; Ting Zhou; Yixin Fu; Minkang Guo; Wu Yang; Dian Zhang; Wenli Fang; Mengli Yao; He Shi; Chengsen Chai; Wei Cheng; Shijia Ding; Tingmei Chen

doi:10.1016/j.omtn.2021.12.036

Self-assembled tetrahedral framework nucleic acid mediates tumor-associated macrophage reprogramming and restores antitumor immunity

Mol Ther Nucleic Acids. 2022 Jan 3:27:763-773. doi: 10.1016/j.omtn.2021.12.036. eCollection 2022 Mar 8.

Authors

Husun Qian¹, Ting Zhou¹, Yixin Fu¹, Minkang Guo², Wu Yang², Dian Zhang¹, Wenli Fang¹, Mengli Yao¹, He Shi¹, Chengsen Chai¹, Wei Cheng³, Shijia Ding¹, Tingmei Chen¹

Affiliations

¹ Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China.
² Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
³ The Center for Clinical Molecular Medical Detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.

Abstract

There is increasing interest in depleting or repolarizing tumor-associated macrophages (TAMs) to generate a proinflammatory effect. However, TAMs usually display an immunosuppressive M2-like phenotype in the tumor microenvironment. Apparently, developing a macrophage-targeting delivery system with immunomodulatory agents is urgent. In this study, an efficient siRNA and CpG ODNs delivery system (CpG-siRNA-tFNA) was prepared with nucleic acid stepwise self-assembled. The tFNA composed of CpG ODNs and siRNA showed a higher stability and an enhanced cellular uptake efficiency. Moreover, the CpG-siRNA-tFNA effectively reprogrammed TAMs toward M1 phenotype polarization with increased proinflammatory cytokine secretion and NF-κB signal pathway activation, which triggers dramatic antitumor immune responses. Additionally, the CpG-siRNA-tFNA exhibited superior antitumor efficacy in a breast cancer xenograft mouse model without obvious systemic side effects. Taken together, CpG-siRNA-tFNA displayed greatly antitumor effect by facilitating TAM polarization toward M1 phenotypes in favor of immunotherapy. Hence, we have developed an efficient therapeutic strategy with immunomodulatory agents for clinical applications.

Keywords: Cancer treatment; CpG ODNs; PI3Kγ siRNA; TAMs; tFNA.