Improving CAR-T cell function through a targeted cytokine delivery system utilizing car target-modified extracellular vesicles

作者：Yuanyuan Zhang, Meijuan Huang, Shujia Zhang, Tianjiao Liu, Shanwei Ye, Yuhang Cheng, Yang Cao, Liting Chen, Li Zhu, Xueyan Sun, Kefeng Shen, Xuhong Qian, Tongjuan Li, Dengju Li, Liang Huang, Wei Mu, Lei Zhao, Jue Wang · 发表于：Experimental Hematology and Oncology · 年份：2025 · DOI：10.1186/s40164-025-00701-z · 被引用次数：4 · 研究领域：CAR-T cell therapy research、Nanowire Synthesis and Applications、Advancements in Semiconductor Devices and Circuit Design

Chimeric antigen receptor (CAR)-T-cell therapy has achieved remarkable clinical success in the treatment of B-cell malignancies; however, its efficacy can be limited by poor T-cell persistence and insufficient antitumor activity in certain cases. Moreover, interleukin-12 (IL-12) is a prominent agent in cancer immunotherapy, but its clinical application is constrained by severe toxicity associated with systemic exposure. In this study, we developed a novel cytokine delivery platform based on CAR target-modified cell-derived extracellular vesicles (EVs) that preferentially bind CAR-T cells to improve CAR-T-cell function. EVs with surface-displayed CD19 and/or IL-12 were successfully generated from HEK-293T cells. Compared with an equivalent concentration of rhIL-12, IL-12 EVs significantly enhanced the effector function of anti-CD19 CAR-T cells in vitro, resulting in increased Interferon-γ (IFN-γ) and TNF-α secretion, cytolytic activity, and T-cell expansion. Additionally, compared with EVs expressing IL-12 alone, EVs co-expressing IL-12 and CD19 (CD19/IL-12 EVs) exhibited superior binding efficiency to CAR-T cells but not to T cells, as indicated by flow cytometry. In xenograft model mice bearing CD19 + Raji tumors, intratumoral injection of CD19/IL-12 EVs resulted in durable antitumor responses and enhanced the in vivo expansion of CAR-T cells, outperforming CD19 EVs, IL-12 EVs and control EVs, without causing systemic toxicity. RNA sequencing (RNA-seq) analysis of CAR-T cell...