Zhao Zhipeng, Li Qian, Qu Chenghao, Jiang Zeyu, Jia Guoqing, Lan Gongde, Luan Yuxia
State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Key Laboratory of Chemical Biology (Ministry of Education), Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Department of Thoracic Surgery, Qilu Hospital of Shandong University, Jinan, China.
Nat Nanotechnol. 2025 May 19. doi: 10.1038/s41565-025-01924-1.
Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of haematological malignancies. Challenges in overcoming physical barriers however greatly limit CAR-T cell efficacy in solid tumours. Here we show that an approach based on collagenase nanogel generally improves the outcome of T cell-based therapies, and specifically of CAR-T cell therapy. The nanogels are created by cross-linking collagenase and subsequently modifying them with a CXCR4 antagonist peptide. These nanogels can bind CAR-T cells via receptor-ligand interaction, resulting in cellular backpack delivery systems. The nanogel backpacks modulate tumoural infiltration and localization of CAR-T cells by surmounting physical barriers and disrupting chemokine-mediated CAR-T cell imprisonment, thereby addressing their navigation deficiency within solid tumours. Our approach offers a promising strategy for pancreatic cancer therapy and holds potential for advancing CAR-T cell therapy towards clinical applications.
嵌合抗原受体（CAR）T细胞疗法彻底改变了血液系统恶性肿瘤的治疗方式。然而，克服物理屏障方面的挑战极大地限制了CAR-T细胞在实体瘤中的疗效。在此，我们表明基于胶原酶纳米凝胶的方法通常可改善基于T细胞的疗法，特别是CAR-T细胞疗法的效果。这些纳米凝胶是通过交联胶原酶并随后用CXCR4拮抗剂肽对其进行修饰而制成的。这些纳米凝胶可通过受体-配体相互作用与CAR-T细胞结合，从而形成细胞背包递送系统。纳米凝胶背包通过克服物理屏障和破坏趋化因子介导的CAR-T细胞滞留来调节CAR-T细胞在肿瘤中的浸润和定位，从而解决它们在实体瘤中的导航缺陷问题。我们的方法为胰腺癌治疗提供了一种有前景的策略，并有望推动CAR-T细胞疗法走向临床应用。
