Convection-enhanced delivery of nanoencapsulated gene locoregionally yielding ErbB2/Her2-specific CAR-macrophages for brainstem glioma immunotherapy

被引:24
作者
Gao, Lin [1 ,2 ]
Shi, Chongdeng [1 ,2 ]
Yang, Zhenmei [1 ,2 ]
Jing, Weiqiang [3 ]
Han, Maosen [1 ,2 ]
Zhang, Jing [1 ,2 ]
Zhang, Cai [1 ,2 ]
Tang, Chunwei [1 ,2 ]
Dong, Yuanmin [1 ,2 ]
Liu, Ying [1 ,2 ]
Chen, Chen [1 ,2 ]
Jiang, Xinyi [1 ,2 ]
机构
[1] Shandong Univ, Cheeloo Coll Med, Sch Pharmaceut Sci, NMPA Key Lab Technol Res & Evaluat Drug Prod, 44 Cultural West Rd, Jinan 250012, Peoples R China
[2] Shandong Univ, Cheeloo Coll Med, Sch Pharmaceut Sci, Key Lab Chem Biol,Minist Educ, 44 Cultural West Rd, Jinan 250012, Peoples R China
[3] Shandong Univ, Qilu Hosp, Cheeloo Coll Med, Dept Urol, 107 Cultural West Rd, Jinan 250012, Peoples R China
基金
中国国家自然科学基金;
关键词
Brainstem gliomas; Macrophages; Immunotherapy; Phenotypic transformation; CAR; TUMOR-ASSOCIATED MACROPHAGES; BREAST-CANCER; T-CELLS; CHEMOTHERAPY;
D O I
10.1186/s12951-023-01810-9
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Locoregional delivery of chimeric antigen receptor (CAR)-modified T (CAR-T) cells has emerged as a promising strategy for brain tumors. However, the complicated ex vivo cell manufacturing procedures and the rapid progression of the disease have limited its broader applications. Macrophages (M phi s) exhibit unique effector functions and a high degree of infiltration within the solid tumor microenvironment (TME), especially in the brain, where M phi s function as structural support, and the main immune effector cells of the CNS represent 5-12% of brain cells. Here, we report a synthetic universal DNA nanocarrier for in situ genetic editing of intratumoral M phi s with an ErbB2-specific CAR to direct their phagocytic activity towards tumors and subsequently initiate a locoregional antitumor immune response. Specifically, we demonstrated that when delivered locoregionally, the RP-182 peptide, located in the shell of a nanoparticle, targeted M phi s and reprogrammed M2-like tumor-associated macrophages (TAMs) to an antitumor M1-like phenotype. Subsequently, the CAR gene-laden DNA nanocomplex can be used to introduce ErbB2-targeted CAR, and the generated CAR-M phi s then act as "living" cures, thereby serially clearing the invasive tumor cells. Our work demonstrates a practical antitumor immunotherapy for brainstem gliomas (BSGs) that may be broadly applicable for patients suffering from other ErbB2-positive solid malignancies.
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页数:16
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