Targeted Codelivery of an Antigen and Dual Agonists by Hybrid Nanoparticles for Enhanced Cancer Immunotherapy

Linhua Zhang, Shengjie Wu, Yu Qin, Fan Fan, Zhiming Zhang, Chenlu Huang, Weihang Ji, Lu Lu, Chun Wang, Hongfan Sun, Xigang Leng, Deling Kong, Dunwan Zhu

Research output: Contribution to journalArticlepeer-review

133 Scopus citations


Among approaches of current cancer immunotherapy, a dendritic cell (DC)-targeted vaccine based on nanotechnology could be a promising way to efficiently induce potent immune responses. To enhance DC targeting and vaccine efficiency, we included imiquimod (IMQ), a toll-like receptor 7/8 (TLR 7/8) agonist, and monophosphoryl lipid A (MPLA), a TLR4 agonist, to synthesize lipid-polymer hybrid nanoparticles using PCL-PEG-PCL and DOTAP (IMNPs) as well as DSPE-PEG-mannose (MAN-IMNPS). The spatiotemporal delivery of MPLA (within the outer lipid layer) to extracellular TLR4 and IMQ (in the hydrophobic core of NPs) to intracellular TLR7/8 can activate DCs synergistically to improve vaccine efficacy. Ovalbumin (OVA) as a model antigen was readily absorbed by positively charged DOTAP and showed a quick release in vitro. Our results demonstrated that this novel nanovaccine enhanced cellular uptake, cytokine production, and maturation of DCs. Compared with the quick metabolism of free OVA-agonists, the depot effect of OVA-IMNPs was observed, whereas MAN-OVA-IMNPs promoted trafficking to secondary lymphoid organs. After immunization with a subcutaneous injection, the nanovaccine, especially MAN-OVA-IMNPs, induced more antigen-specific CD8+ T cells, greater lymphocyte activation, stronger cross-presentation, and more generation of memory T cells, antibody, IFN-γ, and granzyme B. Prophylactic vaccination of MAN-OVA-IMNPs significantly delayed tumor development and prolonged the survival in mice. The therapeutic tumor challenge indicated that MAN-OVA-IMNPs prohibited tumor progression more efficiently than other formulations, and the combination with an immune checkpoint blockade further enhanced antitumor effects. Hence, the DC-targeted vaccine codelivery with IMQ and MPLA adjuvants by hybrid cationic nanoparticles in a spatiotemporal manner is a promising multifunctional antigen delivery system in cancer immunotherapy.

Original languageEnglish (US)
Pages (from-to)4237-4249
Number of pages13
JournalNano letters
Issue number7
StatePublished - Jul 10 2019

Bibliographical note

Funding Information:
This work was supported by the National Natural Science Foundation of China (81671806, 81571793, 81100100, and 51103180), CAMS Initiative for Innovative Medicine (2017-I2M-4-001 and 2017-I2M-3-020), and Tianjin Municipal Natural Science Foundation (15JCZDJC38300).

Publisher Copyright:
© 2019 American Chemical Society.


  • Hybrid nanoparticles
  • TLR agonists
  • antigen
  • cancer immunotherapy
  • vaccine delivery


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