Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 123 Bevier Road, Piscataway, NJ, 08854, USA.
Adv Mater. 2024 May;36(19):e2308377. doi: 10.1002/adma.202308377. Epub 2024 Feb 22.
The removal of dying cells, or efferocytosis, is an indispensable part of resolving inflammation. However, the inflammatory microenvironment of the atherosclerotic plaque frequently affects the biology of both apoptotic cells and resident phagocytes, rendering efferocytosis dysfunctional. To overcome this problem, a chimeric antigen receptor (CAR) macrophage that can target and engulf phagocytosis-resistant apoptotic cells expressing CD47 is developed. In both normal and inflammatory circumstances, CAR macrophages exhibit activity equivalent to antibody blockage. The surface of CAR macrophages is modified with reactive oxygen species (ROS)-responsive therapeutic nanoparticles targeting the liver X receptor pathway to improve their cell effector activities. The combination of CAR and nanoparticle engineering activated lipid efflux pumps enhances cell debris clearance and reduces inflammation. It is further suggested that the undifferentiated CAR-Ms can transmigrate within a mico-fabricated vessel system. It is also shown that our CAR macrophage can act as a chimeric switch receptor (CSR) to withstand the immunosuppressive inflammatory environment. The developed platform has the potential to contribute to the advancement of next-generation cardiovascular disease therapies and further studies include in vivo experiments.
清除死亡细胞（凋亡细胞清除）是消除炎症不可或缺的一部分。然而，动脉粥样硬化斑块的炎症微环境经常影响凋亡细胞和驻留吞噬细胞的生物学特性，使凋亡细胞清除功能失调。为了解决这个问题，开发了一种嵌合抗原受体（CAR）巨噬细胞，它可以靶向和吞噬表达 CD47 的吞噬抵抗性凋亡细胞。在正常和炎症情况下，CAR 巨噬细胞的活性等同于抗体阻断。CAR 巨噬细胞的表面经过修饰，具有针对肝 X 受体途径的活性氧（ROS）响应治疗性纳米颗粒，以提高其细胞效应活性。CAR 和纳米颗粒工程的结合激活了脂质外排泵，增强了细胞碎片清除并减少了炎症。进一步表明，未分化的 CAR-Ms 可以在微制造的血管系统内迁移。还表明，我们的 CAR 巨噬细胞可以作为嵌合开关受体（CSR）来耐受免疫抑制性炎症环境。该平台有可能为下一代心血管疾病治疗方法的发展做出贡献，进一步的研究包括体内实验。
