Han Jun-Hee, Fagan Erinn, Yeom Kyunghwan, Park Ji-Ho
Department of Bio and Brain Engineering and KAIST Institute for Health Science and Technology, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.
ACS Nano. 2025 Dec 9;19(48):40798-40816. doi: 10.1021/acsnano.5c09138. Epub 2025 Nov 25.
Cancer immunotherapy employing chimeric antigen receptor (CAR) technology has achieved significant clinical success in hematologic malignancies, but faces limitations in solid tumors. Among alternative strategies, CAR-macrophage therapy offers distinct advantages in solid tumor settings. However, current ex vivo approaches are hindered by inefficient gene transfer into macrophages and challenges in maintaining an antitumor macrophage phenotype. Here, we report an in situ CAR-macrophage therapy via codelivery of mRNA and immunostimulant. By leveraging lipid nanoparticles (LNPs) designed to selectively transfect tumor-associated macrophages, we circumvent extensive ex vivo manipulation and achieve robust CAR expression directly within the tumor microenvironment. Furthermore, codelivery of a stimulator of interferon genes (STING) agonist amplifies local immune activation, leading to reinforced CAR-macrophage functionality and enhanced antitumor effects in a mouse melanoma model. This in vivo strategy addressed key obstacles of CAR-macrophage therapy in solid tumors by enabling direct cellular targeting, potent immunomodulation, and simplified manufacturing. Our findings suggest an LNP-enabled approach for CAR-macrophage immunotherapy to overcome the limitations associated with conventional CAR-T cell therapies.
采用嵌合抗原受体（CAR）技术的癌症免疫疗法在血液系统恶性肿瘤中取得了显著的临床成功，但在实体瘤治疗中面临局限性。在其他替代策略中，CAR巨噬细胞疗法在实体瘤治疗中具有独特优势。然而，目前的体外方法受到巨噬细胞基因转染效率低下以及维持抗肿瘤巨噬细胞表型方面挑战的阻碍。在此，我们报告一种通过共递送信使核糖核酸（mRNA）和免疫刺激剂进行原位CAR巨噬细胞治疗的方法。通过利用设计用于选择性转染肿瘤相关巨噬细胞的脂质纳米颗粒（LNP），我们规避了广泛的体外操作，并在肿瘤微环境中直接实现了强大的CAR表达。此外，共递送干扰素基因刺激剂（STING）激动剂可放大局部免疫激活，从而增强CAR巨噬细胞的功能，并在小鼠黑色素瘤模型中增强抗肿瘤效果。这种体内策略通过实现直接细胞靶向、强效免疫调节和简化生产，解决了CAR巨噬细胞疗法在实体瘤治疗中的关键障碍。我们的研究结果表明，一种基于LNP的方法可用于CAR巨噬细胞免疫疗法，以克服与传统CAR-T细胞疗法相关的局限性。
