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Nano Research 2022, 15(9): 8326-8335 https://doi.org/10.1007/s12274-022-4504-2
Research Article | Issue | Published: 20 June 2022

Systematic co-delivery of dual agonists to enhance cancer immunotherapy

Show Author's Information Xiangxia Li1,  Guiyuan Chen1,  Yangyi Wang2,  Lanhong Su1,  Bo Chen1,  Kecheng Wu1,  Yun Xing1,  Zechenxi Song1,  Ruike Dai1,  Tianxin Liu1,  Jiaao Zhao1,  Zhe Xie1,  Peijie Zhou2,  Xiaoping Xia3,4,5( ),  Yuanzeng Min1,2( )
Department of Chemistry, University of Science and Technology of China, Hefei 230026, China
The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
Anhui Provincial Children’s Hospital, Hefei 230051, China
Children’s Hospital of Fudan University Anhui Hospital, Hefei 230051, China
Children’s Hospital of Anhui Medical University, Hefei 230051, China
Keywords:
drug delivery, cancer immunotherapy, toll-like receptors (TLRs) agonists, mesoporous silica nanoparticles (MSNs), tumor immunosuppressive microenvironment (TIME)
Topics:
Drug delivery
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Li X, Chen G, Wang Y, et al. Systematic co-delivery of dual agonists to enhance cancer immunotherapy. Nano Research, 2022, 15(9): 8326-8335. https://doi.org/10.1007/s12274-022-4504-2
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Abstract Full text Electronic supplementary material About this article

In the tumor immunosuppressive microenvironment (TIME), antigen presenting cells (APCs) usually exhibit a tumor suppressor phenotype. Toll-like receptors (TLRs) agonists could reprogram M2-type macrophages to M1-type and stimulate dendritic cells (DCs) maturation. The combination of TLR7/8 and TLR9 agonists seems to have synergistic therapeutic efficacy. Here, we designed a lipid-coated mesoporous silica nanoparticle (MSNs@Lipo) for the co-delivery of TLR7/8 agonist resiquimod (R848) and TLR9 agonist CpG oligodeoxynucleotides (ODNs) (CpG@MSNs-R@L-M). R848 was firstly conjugated onto the nanoparticle via silane chemistry, which is acidic responsive drug release. Then, CpG was loaded onto the nanoparticle through the positive charge mainly from TLR7/8 agonist R848. Our in vitro experiments further indicated that both drugs have acid-responsive release properties and could be taken up by DCs and located on the endosomes of APCs. More importantly, CpG@MSNs-R@L-M could significantly improve the antitumor efficacy in B16F10 melanoma model. The mechanistic study demonstrated that CpG@MSNs-R@L-M could remarkably modulate the TIME by promoting the maturation of DCs and repolarizing macrophages from M2 to M1 phenotype and facilitating the infiltration of tumor cytotoxic T cells. It was concluded that in comparison to single agonist, the co-delivery of dual agonists, CpG and R848, can improve anti-tumor immune responses for cancer immunotherapy.


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Electronic supplementary material
About this article

Systematic co-delivery of dual agonists to enhance cancer immunotherapy

Show Author's information Xiangxia Li1, Guiyuan Chen1, Yangyi Wang2, Lanhong Su1, Bo Chen1, Kecheng Wu1, Yun Xing1, Zechenxi Song1, Ruike Dai1, Tianxin Liu1, Jiaao Zhao1, Zhe Xie1, Peijie Zhou2, Xiaoping Xia3,4,5( ), Yuanzeng Min1,2( )
Department of Chemistry, University of Science and Technology of China, Hefei 230026, China
The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
Anhui Provincial Children’s Hospital, Hefei 230051, China
Children’s Hospital of Fudan University Anhui Hospital, Hefei 230051, China
Children’s Hospital of Anhui Medical University, Hefei 230051, China

Abstract

In the tumor immunosuppressive microenvironment (TIME), antigen presenting cells (APCs) usually exhibit a tumor suppressor phenotype. Toll-like receptors (TLRs) agonists could reprogram M2-type macrophages to M1-type and stimulate dendritic cells (DCs) maturation. The combination of TLR7/8 and TLR9 agonists seems to have synergistic therapeutic efficacy. Here, we designed a lipid-coated mesoporous silica nanoparticle (MSNs@Lipo) for the co-delivery of TLR7/8 agonist resiquimod (R848) and TLR9 agonist CpG oligodeoxynucleotides (ODNs) (CpG@MSNs-R@L-M). R848 was firstly conjugated onto the nanoparticle via silane chemistry, which is acidic responsive drug release. Then, CpG was loaded onto the nanoparticle through the positive charge mainly from TLR7/8 agonist R848. Our in vitro experiments further indicated that both drugs have acid-responsive release properties and could be taken up by DCs and located on the endosomes of APCs. More importantly, CpG@MSNs-R@L-M could significantly improve the antitumor efficacy in B16F10 melanoma model. The mechanistic study demonstrated that CpG@MSNs-R@L-M could remarkably modulate the TIME by promoting the maturation of DCs and repolarizing macrophages from M2 to M1 phenotype and facilitating the infiltration of tumor cytotoxic T cells. It was concluded that in comparison to single agonist, the co-delivery of dual agonists, CpG and R848, can improve anti-tumor immune responses for cancer immunotherapy.

Keywords: drug delivery, cancer immunotherapy, toll-like receptors (TLRs) agonists, mesoporous silica nanoparticles (MSNs), tumor immunosuppressive microenvironment (TIME)

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Publication history
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Acknowledgements

Publication history

Received: 23 February 2022
Revised: 04 May 2022
Accepted: 04 May 2022
Published: 20 June 2022
Issue date: September 2022

Copyright

© Tsinghua University Press 2022

Acknowledgements

Acknowledgements

This work was supported by a Start-Up grant KY2060000124 and KJ2060190030 from University of Science and Technology of China and supported by National Natural Science Foundation of China (Nos. 31971299, GG2065010001, GG2060190386, and 82102953) and Fundamental Research Funds for the Central Universities (Nos. WK2060190101, WY2060190092, and WK9110000144).

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