Gene-activating nanomedicine for the tumor-oriented infiltration of T cells to enhance immunotherapy against solid tumors

作者：Zhang, Yue; Zhao, Gui; Liu, Jing; Zhang, Hou-Bing; Wang, Yue; Luo, Ying-Li; Lu, Zi-Dong; Du, Xiao-Jiao; Shen, Song; Du, Jin-Zhi; Xu, Cong-Fei^*; Wang, Jun^*

来源：Nano Today, 2023, 52: 101992.

DOI：10.1016/j.nantod.2023.101992

• Nanoparticle
• Gene delivery
• CRISPR activation
• T cell infiltration
• Cancer immunotherapy

The insufficient infiltration of T cells in solid tumors hinders the therapeutic efficacy of immune checkpoint blockade (ICB) antibodies and chimeric antigen receptor (CAR)-T cells. Promoting T or CAR-T cells to efficiently and specifically migrate into solid tumors is critical for improving current immunotherapies, which remains a challenge. Herein, we proposed a CRISPR-based transcriptional activation (CRISPRa) nanomedicine for mobi-lizing tumor cells to recruit T cells by activating the expression of T cell chemokines CXC-chemokine ligand (CXCL) 9, CXCL10, and CXCL11. We demonstrated that the CRISPRa nanomedicine could dramatically upre-gulate the expression of these T cell chemokines in tumor cells, thereby facilitating T cell migration directionally into solid tumors. Intratumoral injection of the CRISPRa nanomedicine inhibited the growth of different solid tumors including melanoma, pancreatic, colonic, and breast cancers. Moreover, tumor-specific versions of the CRISPRa nanomedicine possessing the ability to upregulate the T cell chemokine expression only in tumors rather than normal tissues or cells were constructed. Systemic injection of the tumor-specific CRISPRa nano -medicine specifically recruited T or CAR-T cells into solid tumors and improved the therapeutic effects of ICB antibodies (anti-PD-L1 or anti-CTLA4) and CAR-T cells. Thus, the gene-activating nanomedicine provides a promising strategy for enhancing T cell infiltration to improve current immunotherapies against solid tumors.