Gao Yang, Hu Jianlin, An Ning, Wen Xinyu, Li Chunrui
Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
Key Laboratory of Vascular Aging, Tongji Hospital, Tongji Medical College, Ministry of Education, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
Biomark Res. 2026 Jan 27;14(1):23. doi: 10.1186/s40364-026-00899-y.
Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment landscape for hematologic malignancies. Nonetheless, its broad clinical adoption is constrained by the logistical, financial, and safety burdens associated with ex vivo cell manufacturing. In vivo CAR-T engineering has emerged as a transformative alternative, enabling the direct reprogramming of endogenous T cells through systemic delivery of CAR-encoding constructs via viral or non-viral vectors. This strategy eliminates the need for leukapheresis, genetic modification, and reinfusion, paving the way for simplified, scalable, and potentially “off-the-shelf” immunotherapies. While challenges such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) remain shared hurdles, in vivo approaches introduce added complexities, including vector immunogenicity and innate immune sensing. By leveraging RNA-based platforms, in vivo CAR-T engineering is evolving into a programmable immunotherapy modality beyond oncology. At the same time, regulatory frameworks for systemic in vivo reprogramming remain underdeveloped, underscoring the need for harmonized guidelines that balance innovation with patient safety. This review synthesizes progress across major delivery platforms, analyzes key translational and regulatory barriers specific to in vivo approaches, and highlights emerging innovations in vector tropism, immune modulation, and scalable manufacturing. As the field matures, in vivo CAR-T strategies may unlock broader therapeutic applications across oncology and autoimmune disease, redefining the accessibility and precision of cellular immunotherapy.
嵌合抗原受体（CAR）-T细胞疗法已经改变了血液系统恶性肿瘤的治疗格局。尽管如此，其广泛的临床应用受到与体外细胞制造相关的后勤、财务和安全负担的限制。体内CAR-T工程已成为一种变革性的替代方案，通过病毒或非病毒载体全身递送CAR编码构建体，能够直接对内源性T细胞进行重编程。这种策略消除了白细胞分离、基因改造和回输的需求，为简化、可扩展且可能“现成可用”的免疫疗法铺平了道路。虽然诸如细胞因子释放综合征（CRS）和免疫效应细胞相关神经毒性综合征（ICANS）等挑战仍然是共同的障碍，但体内方法引入了额外的复杂性，包括载体免疫原性和先天免疫感知。通过利用基于RNA的平台，体内CAR-T工程正在发展成为一种超越肿瘤学的可编程免疫治疗方式。与此同时，全身体内重编程的监管框架仍不发达，这突出了制定平衡创新与患者安全的统一指南的必要性。本综述综合了主要递送平台的进展，分析了体内方法特有的关键转化和监管障碍，并强调了载体趋向性、免疫调节和可扩展制造方面的新兴创新。随着该领域的成熟，体内CAR-T策略可能会在肿瘤学和自身免疫性疾病中解锁更广泛的治疗应用，重新定义细胞免疫治疗的可及性和精确性。
