TY - JOUR
T1 - Dual-Targeted Lipid Nanotherapeutic Boost for Chemo-Immunotherapy of Cancer
AU - Yong, Seok Beom
AU - Ramishetti, Srinivas
AU - Goldsmith, Meir
AU - Diesendruck, Yael
AU - Hazan-Halevy, Inbal
AU - Chatterjee, Sushmita
AU - Somu Naidu, Gonna
AU - Ezra, Assaf
AU - Peer, Dan
N1 - Funding Information:
The authors thank V. Holdengreber for assistance with the transmission electron microscopy analysis. This work was supported by the ERC grant LeukoTheranostics (Award No. 647410) to D.P. and the National Research Foundation of Korea, Postdoctoral Fellowship Program (2021R1A6A3A03039300) to S.‐B.Y. All animal protocols were approved by the Tel Aviv University, Institutional Animal Care and Usage Committee and in accordance with current regulations and standards of the Israel Ministry of Health.
Publisher Copyright:
© 2022 The Authors. Advanced Materials published by Wiley-VCH GmbH.
PY - 2022/4/1
Y1 - 2022/4/1
N2 - Chemo-immunotherapy is a combination of “standard-of-care” chemotherapy with immunotherapy and it is considered the most advanced therapeutic modality for various types of cancers. However, many cancer patients still poorly respond to current regimen of chemo-immunotherapy and suggest nanotherapeutics as a boosting agent. Recently, heme oxygenase-1 (HO1) is shown to act as an immunotherapeutic molecule in tumor myeloid cells, in addition to general chemoresistance function in cancer cells suggesting that HO1-targeted therapeutics can become a novel, optimal strategy for boosting chemo-immunotherapy in the clinic. Currently the available HO1-inhibitors demonstrate serious adverse effects in clinical use. Herein, tumor myeloid cell- and cancer cell-dual targeted HO1-inhibiting lipid nanotherapeutic boost (T-iLNTB) is developed using RNAi-loaded lipid nanoparticles. T-iLNTB-mediated HO1-inhibition sensitizes cancer cells to “standard-of-care” chemotherapeutics by increasing immunogenic cell death, and directly reprograms tumor myeloid cells with distinguished phenotype. Furthermore, tumor myeloid cell reprogramming by T-iLNTB induces CD8+ cytotoxic T cell recruitment, which drives “Cold-to-Hot” transition and correlates with improved responsiveness to immune checkpoint inhibitor in combination therapy. Finally, ex vivo study proves that HO1-inhibition directly affects tumor macrophage differentiation. This study demonstrates the potential of T-iLNTB as a novel therapeutic modality for boosting chemo-immunotherapy.
AB - Chemo-immunotherapy is a combination of “standard-of-care” chemotherapy with immunotherapy and it is considered the most advanced therapeutic modality for various types of cancers. However, many cancer patients still poorly respond to current regimen of chemo-immunotherapy and suggest nanotherapeutics as a boosting agent. Recently, heme oxygenase-1 (HO1) is shown to act as an immunotherapeutic molecule in tumor myeloid cells, in addition to general chemoresistance function in cancer cells suggesting that HO1-targeted therapeutics can become a novel, optimal strategy for boosting chemo-immunotherapy in the clinic. Currently the available HO1-inhibitors demonstrate serious adverse effects in clinical use. Herein, tumor myeloid cell- and cancer cell-dual targeted HO1-inhibiting lipid nanotherapeutic boost (T-iLNTB) is developed using RNAi-loaded lipid nanoparticles. T-iLNTB-mediated HO1-inhibition sensitizes cancer cells to “standard-of-care” chemotherapeutics by increasing immunogenic cell death, and directly reprograms tumor myeloid cells with distinguished phenotype. Furthermore, tumor myeloid cell reprogramming by T-iLNTB induces CD8+ cytotoxic T cell recruitment, which drives “Cold-to-Hot” transition and correlates with improved responsiveness to immune checkpoint inhibitor in combination therapy. Finally, ex vivo study proves that HO1-inhibition directly affects tumor macrophage differentiation. This study demonstrates the potential of T-iLNTB as a novel therapeutic modality for boosting chemo-immunotherapy.
KW - HO1-targeted nanotherapeutics
KW - cancer-targeted therapy
KW - chemo-immunotherapy
KW - ionizable lipid nanoparticle
KW - targeted lipid nanoparticle
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U2 - 10.1002/adma.202106350
DO - 10.1002/adma.202106350
M3 - Article
C2 - 35044699
AN - SCOPUS:85124521924
VL - 34
JO - Advanced Materials
JF - Advanced Materials
SN - 0935-9648
IS - 13
M1 - 2106350
ER -