《生命科学》 2026, 38(10): 1709-1717
体内CAR-T细胞疗法递送载体的研究进展和挑战
摘 要：
嵌合抗原受体 T 细胞（CAR-T）疗法在癌症领域已实现临床应用，在自身免疫性疾病、纤维化和抗衰老等领域也有着广泛的研究与应用前景。但传统体外CAR-T疗法存在制备工艺复杂、生产条件严格和生产周期漫长等缺点，造成其成本高昂。体内CAR-T疗法实现体内原位生成CAR-T细胞，成为“即用型”免疫治疗方案。本文首先系统综述了体内CAR-T疗法的技术框架，重点聚焦病毒与非病毒两种递送载体的临床前研究进展，探讨了目前递送载体存在的脱靶效应、安全性差以及载药量小等问题，并最终指出联合CRISPR/Cas9 等基因编辑手段及增强载体靶向性和稳定性的发展思路，以推进其临床前开发及临床应用，从而更好地造福肿瘤患者。
通讯作者：刘滨磊 , Email:liubl@hbut.edu.cn
Abstract:
Chimeric antigen receptor T (CAR-T) cell therapy is a transformative immunotherapeutic modality with successful clinical translation for cancer treatment, and it also has extensive application potential in autoimmune diseases, tissue fibrosis and anti-aging disorders. However, conventional ex vivo CAR-T cell therapy suffers from several deficiencies, namely the necessity of lymphodepletion preconditioning and the difficulty in cost reduction, which renders it incapable of providing rapid and widespread treatment for tumor patients. Allogeneic ex vivo CAR-T products, though partially overcoming the limitations of autologous counterparts, are associated with severe adverse effects including graft-versus-host disease (GVHD) and host-versus-graft reaction (HVGR). These complications induce multi-organ damage and shorten in vitro CAR-T cell survival respectively, becoming major bottlenecks for their clinical translation. Against this backdrop, in vivo CAR-T therapy has emerged as a promising "off-the-shelf" alternative, which achieves in situ generation of tumorreactive CAR-T cells by delivering CAR-encoding genetic materials into patients’ endogenous T cells via specialized gene delivery vectors. This novel approach obviates lymphodepletion preconditioning, simplifies therapeutic process, and enables scalable treatment for a broader patient population. Herein, we systematically delineate the technical framework of in vivo CAR-T therapy, focusing on the latest preclinical advances of viral and non-viral gene delivery vectors. Viral vectors, the most mature delivery system for CAR-T therapy, mainly include lentiviral vectors (LV) and adeno-associated viral vectors (AAV). Rational engineering of LV envelope and AAV capsid proteins has markedly enhanced T cell-specific transduction efficiency, mitigated off-target effects and improved biosafety, with preclinical studies validating their robust efficacy in
eradicating malignant cells in hematological tumor models. Non-viral vectors, a promising next-generation substitute, comprise lipid nanoparticles (LNP), cationic polymers and exosomes, which feature low cytotoxicity, reduced immunogenicity and minimal insertional mutagenesis risk, yielding encouraging preclinical outcomes in tumor and fibrotic disease treatment. We further elaborate on critical challenges for these vectors, including off-target effects, inadequate biosafety, limited cargo capacity, low non-viral transfection efficiency, transient gene expression and T cell exhaustion impairing long-term efficacy. Finally, we propose key strategies: integrating CRISPR/Cas9-mediated gene editing to optimize in situ CAR-T functional persistence, advancing vector engineering to enhance targeting, stability and cargo loading, and exploring hybrid delivery platforms amalgamating viral and non-viral advantages. These strategies are expected to accelerate the preclinical and clinical translation of in vivo CAR-T therapy, elevate its safety and efficacy, and provide more accessible immunotherapeutic options for cancer patients.
Communication Author：LIU Bin-Lei , Email:liubl@hbut.edu.cn
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