Modulation of intrinsic inhibitory checkpoints using nano-carriers to unleash NK cell activity

Guy Biber, Batel Sabag, Anat Raiff, Aviad Ben-Shmuel, Abhishek Puthenveetil, Jennifer I.C. Benichou, Tammir Jubany, Moria Levy, Shiran Killner, Mira Barda-Saad

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


Natural killer (NK) cells provide a powerful weapon mediating immune defense against viral infections, tumor growth, and metastatic spread. NK cells demonstrate great potential for cancer immunotherapy; they can rapidly and directly kill cancer cells in the absence of MHC-dependent antigen presentation and can initiate a robust immune response in the tumor microenvironment (TME). Nevertheless, current NK cell-based immunotherapies have several drawbacks, such as the requirement for ex vivo expansion of modified NK cells, and low transduction efficiency. Furthermore, to date, no clinical trial has demonstrated a significant benefit for NK-based therapies in patients with advanced solid tumors, mainly due to the suppressive TME. To overcome current obstacles in NK cell-based immunotherapies, we describe here a non-viral lipid nanoparticle-based delivery system that encapsulates small interfering RNAs (siRNAs) to gene silence the key intrinsic inhibitory NK cell molecules, SHP-1, Cbl-b, and c-Cbl. The nanoparticles (NPs) target NK cells in vivo, silence inhibitory checkpoint signaling molecules, and unleash NK cell activity to eliminate tumors. Thus, the novel NP-based system developed here may serve as a powerful tool for future NK cell-based therapeutic approaches.

Original languageEnglish
Article numbere14073
Number of pages18
JournalEMBO Molecular Medicine
Issue number1
StatePublished - 11 Jan 2022

Bibliographical note

Funding Information:
The authors thank Prof. Angel Porgador, Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben‐Gurion University of the Negev, Beer Sheva, Israel, for providing us with the NKp46 hybridoma. Dr. Omri Matalon, Dr. Itay Lazar, Dr. Alex Vorvak from Bar‐Ilan University, Dr. Liron Miller, and Mr. Hekmatian Nassir from the blood bank and transfusion center of Sheba Medical Center, Israel, for their technical assistance. This research was funded by the Israel Innovation Authority.

Publisher Copyright:
© 2021 The Authors. Published under the terms of the CC BY 4.0 license.


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