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.
Yun Chang  1  2 ,  Xuechao Cai  3 ,  Ramizah Syahirah  4 ,  Yuxing Yao  5 ,  Yang Xu  6 ,  Gyuhyung Jin  1  2 ,  Vijesh J Bhute  7 ,  Sandra Torregrosa-Allen  2 ,  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-Adefeso  14 ,  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. [email protected].
  • 10. The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA, 16802, USA. [email protected].
  • 11. Department of Biology, The Pennsylvania State University, University Park, PA, 16802, USA. [email protected].
  • 12. William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, 43210, USA. [email protected].
  • 13. Sustainability Institute, The Ohio State University, Columbus, OH, 43210, USA. [email protected].
  • 14. Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA. [email protected].
  • 15. Davidson School of Chemical Engineering, Purdue University, West Lafayette, IN, 47907, USA. [email protected].
  • 16. Purdue University Institute for Cancer Research, West Lafayette, IN, 47907, USA. [email protected].
PMID: 37080958 DOI: 10.1038/s41467-023-37872-4
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.