Zhou Ying, Guo Yuxin, Chen Lufei, Zhang Xiaoli, Wu Wei, Yang Zhimin, Li Xuejie, Wang Yuanzhuo, Hu Zhiyuan, Wang Zihua
Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian 350122, China.
CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China.
Theranostics. 2022 Jul 18;12(12):5488-5503. doi: 10.7150/thno.73104. eCollection 2022.
Cancer immunotherapy has demonstrated significant antitumor activity in a variety of tumors; however, extensive infiltration of immunosuppressive tumor-associated macrophages (TAMs) in the glioblastoma (GBM) tumor microenvironment (TME) and the existence of the blood-brain barrier (BBB) might lead to failure of the checkpoint blockade therapy. Herein, we have developed a smart "Trojan horse" BBB-permeable nanocapsule termed "NAcp@CD47" to deliver anti-CD47 antibodies and stimulator of interferon genes (STING) agonists into GBM tissues in a stealth-like manner to reshaped the immune microenvironment by switching the phenotype of microglia and macrophages. Results: Both in vitro and in vivo studies demonstrate that NAcp@CD47 could effectively penetrate the BBB, increase the polarization of M1-phenotype TAMs, help reduce tumor immunosuppression, and inhibit the orthotopic GBM growth by phagocytosis of macrophages and microglia. Our findings indicate that the well-designed NAcp@CD47 not only enhances the phagocytosis of cancer cells but also efficiently enhance antitumor immunogenicity and reverses immune suppression to convert uninflamed "cold" tumors into "hot" tumors.
癌症免疫疗法已在多种肿瘤中展现出显著的抗肿瘤活性；然而，胶质母细胞瘤（GBM）肿瘤微环境（TME）中免疫抑制性肿瘤相关巨噬细胞（TAM）的广泛浸润以及血脑屏障（BBB）的存在可能导致检查点阻断疗法失败。在此，我们开发了一种智能的、可穿透血脑屏障的“特洛伊木马”纳米胶囊，称为“NAcp@CD47”，以隐形方式将抗CD47抗体和干扰素基因刺激剂（STING）激动剂递送至GBM组织，通过改变小胶质细胞和巨噬细胞的表型来重塑免疫微环境。结果：体外和体内研究均表明，NAcp@CD47能够有效穿透血脑屏障，增加M1型TAM的极化，有助于减轻肿瘤免疫抑制，并通过巨噬细胞和小胶质细胞的吞噬作用抑制原位GBM生长。我们的研究结果表明，精心设计的NAcp@CD47不仅增强了癌细胞的吞噬作用，还能有效增强抗肿瘤免疫原性，并逆转免疫抑制，将未发炎的“冷”肿瘤转化为 “热” 肿瘤。
