A Spatiotemporally Controllable DNA Hydrogel Mesh for Focused Antimetastasis Therapy of Cancer

Cancer is one of the most commonly diagnosed diseases with high mortality, and approximately 50% of patients are prone to present metastasis after various treatments. The shedding of circulating tumor cells (CTCs) during tumor therapy is the root cause of metastasis. In this work, we proposed a focused antimetastasis therapy strategy based on a spatiotemporally controllable DNA hydrogel mesh (SNARE: just like a turtle trapped in the jar) in vivo. The whole treatment process was performed in the limited space of the SNARE, which realized the immobilization of CTCs in situ for antimetastasis effects. A stimulus-responsive reversible drug nanocarrier module and an epithelial cell adhesion molecule (EpCAM) aptamer recognition module endowed the SNARE with spatiotemporal controllability for precise tumor cell immobilization. The SNARE also activated a robust immune performance through overcoming immune escape, inducing immunogenic cell death, and enhancing the cGAS-STING pathway to assist the CTC immobilization strategy for a better antimetastasis efficiency. Moreover, it was found that the EpCAM aptamer could realize the endogenous PD-L1 regulation through the epidermal growth factor receptor pathway, and the immunotherapy efficiency was further intensified by the ordered networks of the DNA hydrogel. This work provided a focused antimetastasis therapy strategy for cancer through the immobilization of CTCs in a limited space, which also gave insight into alternative development approaches of immune checkpoint inhibitors.

癌症是最常见的高致死性确诊疾病之一，约50%的患者在接受各类治疗后易发生转移。肿瘤治疗过程中循环肿瘤细胞（circulating tumor cells, CTCs）的脱落是转移发生的根本原因。本研究提出了一种基于体内时空可控DNA水凝胶网格（SNARE：恰似困于罐中的乌龟）的靶向抗转移治疗策略。整个治疗过程在SNARE的有限空间内完成，实现了CTCs的原位固定，从而发挥抗转移效果。刺激响应型可逆药物纳米载体模块与上皮细胞黏附分子（epithelial cell adhesion molecule, EpCAM）适配体识别模块，赋予SNARE时空可控性，可实现精准的肿瘤细胞固定。SNARE还可通过克服免疫逃逸、诱导免疫原性细胞死亡、激活cGAS-STING通路来激活强效免疫应答，辅助CTCs固定策略以获得更优的抗转移效率。此外，研究发现EpCAM适配体可通过表皮生长因子受体通路实现内源性程序性死亡配体1（programmed death-ligand 1, PD-L1）的调控，而DNA水凝胶的有序网络结构进一步强化了免疫治疗效果。本研究通过在有限空间内固定CTCs，为癌症抗转移治疗提供了一种靶向策略，同时也为免疫检查点抑制剂的替代开发思路提供了新的研究见解。