Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China.
Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore 117597, Singapore.
Sci Adv. 2023 Aug 9;9(32):eadh2413. doi: 10.1126/sciadv.adh2413.
Equipping multiple functionalities on adoptive effector cells is essential to overcome the complex immunological barriers in solid tumors for superior antitumor efficacy. However, current cell engineering technologies cannot endow these functionalities to cells within a single step because of the different spatial distributions of targets in one cell. Here, we present a core-shell anti-phagocytosis-blocking repolarization-resistant membrane-fusogenic liposome (ARMFUL) to achieve one-step multiplexing cell engineering for multifunctional cell construction. Through fusing with the M1 macrophage membrane, ARMFUL inserts an anti-CD47 (aCD47)-modified lipid shell onto the surface and simultaneously delivers colony-stimulating factor 1 receptor inhibitor BLZ945-loaded core into the cytoplasm. The surface-presenting aCD47 boosts macrophage's phagocytosis against the tumor by blocking CD47. The cytoplasm-located BLZ945 prompts its polarization resistance to M2 phenotype in the immunosuppressive microenvironment via inactivating the intracellular M2 polarization signaling pathway. This ARMFUL provides a versatile cell engineering platform to customize multimodal cellular functions for enhanced adoptive cell therapy.
为了克服实体瘤中复杂的免疫障碍，以实现优异的抗肿瘤疗效，在过继效应细胞上装备多种功能至关重要。然而，由于一个细胞内靶标的空间分布不同，当前的细胞工程技术无法在单个步骤中赋予这些功能。在这里，我们提出了一种核壳型抗吞噬、阻断再极化、耐药性的膜融合脂囊泡（ARMFUL），以实现一步式多重细胞工程，用于多功能细胞构建。通过与 M1 巨噬细胞膜融合，ARMFUL 将一种抗 CD47（aCD47）修饰的脂质壳插入表面，并同时将含有集落刺激因子 1 受体抑制剂 BLZ945 的核心递送至细胞质中。表面呈现的 aCD47 通过阻断 CD47 来增强巨噬细胞对肿瘤的吞噬作用。位于细胞质中的 BLZ945 通过失活细胞内 M2 极化信号通路，促使其在免疫抑制微环境中抵抗 M2 表型的极化。这种 ARMFUL 提供了一个通用的细胞工程平台，用于定制多种细胞功能，以增强过继细胞治疗。
