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; Xiaoping Bao

doi:10.1038/s41467-023-37872-4

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

Nat Commun. 2023 Apr 20;14(1):2266. doi: 10.1038/s41467-023-37872-4.

Authors

Yun Chang^{1

2}, Xuechao Cai³, Ramizah Syahirah⁴, Yuxing Yao⁵, Yang Xu⁶, Gyuhyung Jin^{1

2}, Vijesh J Bhute⁷, Sandra Torregrosa-Allen², Bennett D Elzey^{2

8}, You-Yeon Won^{1

2}, Qing Deng^{2

4}, Xiaojun Lance Lian^{9

10

11}, Xiaoguang Wang^{12

13}, Omolola Eniola-Adefeso¹⁴, Xiaoping Bao^{15

16}

Affiliations

¹ Davidson School of Chemical Engineering, Purdue University, West Lafayette, IN, 47907, USA.
² Purdue University Institute for Cancer Research, West Lafayette, IN, 47907, USA.
³ Tongji University Cancer Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
⁴ Department of Biological Sciences, Purdue University, West Lafayette, IN, 47907, USA.
⁵ Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, 91125, USA.
⁶ William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, 43210, USA.
⁷ Department of Chemical Engineering, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK.
⁸ Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, 47907, USA.
⁹ Department of Biomedical Engineering, The Pennsylvania State University, University Park, PA, 16802, USA. lian@psu.edu.
¹⁰ The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA, 16802, USA. lian@psu.edu.
¹¹ Department of Biology, The Pennsylvania State University, University Park, PA, 16802, USA. lian@psu.edu.
¹² William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, 43210, USA. wang.12206@osu.edu.
¹³ Sustainability Institute, The Ohio State University, Columbus, OH, 43210, USA. wang.12206@osu.edu.
¹⁴ Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA. lolaa@umich.edu.
¹⁵ Davidson School of Chemical Engineering, Purdue University, West Lafayette, IN, 47907, USA. bao61@purdue.edu.
¹⁶ Purdue University Institute for Cancer Research, West Lafayette, IN, 47907, USA. bao61@purdue.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain Neoplasms* / drug therapy
Female
Glioblastoma* / drug therapy
Glioblastoma* / genetics
Humans
Immunotherapy
Immunotherapy, Adoptive
Mice
Nanoparticles* / therapeutic use
Neutrophils
T-Lymphocytes
Tumor Microenvironment

Abstract

Publication types

MeSH terms

Grants and funding