CAR-neutrophil mediated delivery of tumor-microenvironment responsive nanodrugs for glioblastoma chemo-immunotherapy

Yun Chang, Xuechao Cai, Ramizah Syahirah, Yuxing Yao, Yang Xu, Gyuhyung Jin, Vijesh J. Bhute, Sandra Torregrosa-Allen, Bennett D. Elzey, You-Yeon Won, Qing Deng, Xiaojun Lance Lian (), Xiaoguang Wang (), Omolola Eniola-Adefeso () and Xiaoping Bao ()
Additional contact information
Yun Chang: Purdue University
Xuechao Cai: Tongji University Cancer Center, Shanghai Tenth People’s Hospital, Tongji University School of Medicine
Ramizah Syahirah: Purdue University
Yuxing Yao: California Institute of Technology
Yang Xu: The Ohio State University
Gyuhyung Jin: Purdue University
Vijesh J. Bhute: Imperial College London, South Kensington Campus
Sandra Torregrosa-Allen: Purdue University Institute for Cancer Research
Bennett D. Elzey: Purdue University Institute for Cancer Research
You-Yeon Won: Purdue University
Qing Deng: Purdue University Institute for Cancer Research
Xiaojun Lance Lian: The Pennsylvania State University
Xiaoguang Wang: The Ohio State University
Omolola Eniola-Adefeso: University of Michigan
Xiaoping Bao: Purdue University

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Glioblastoma (GBM) is one of the most aggressive and lethal solid tumors in human. While efficacious therapeutics, such as emerging chimeric antigen receptor (CAR)-T cells and chemotherapeutics, have been developed to treat various cancers, their effectiveness in GBM treatment has been hindered largely by the blood-brain barrier and blood-brain-tumor barriers. Human neutrophils effectively cross physiological barriers and display effector immunity against pathogens but the short lifespan and resistance to genome editing of primary neutrophils have limited their broad application in immunotherapy. Here we genetically engineer human pluripotent stem cells with CRISPR/Cas9-mediated gene knock-in to express various anti-GBM CAR constructs with T-specific CD3ζ or neutrophil-specific γ-signaling domains. CAR-neutrophils with the best anti-tumor activity are produced to specifically and noninvasively deliver and release tumor microenvironment-responsive nanodrugs to target GBM without the need to induce additional inflammation at the tumor sites. This combinatory chemo-immunotherapy exhibits superior and specific anti-GBM activities, reduces off-target drug delivery and prolongs lifespan in female tumor-bearing mice. Together, this biomimetic CAR-neutrophil drug delivery system is a safe, potent and versatile platform for treating GBM and possibly other devastating diseases.

Date: 2023
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DOI: 10.1038/s41467-023-37872-4

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