Abstract
The success of therapeutic cancer vaccines hinges on overcoming the immunosuppressive tumor microenvironment (TME) and activating robust, durable cellular immunity. Here, we engineered a highly translatable vaccine adjuvant delivery system (LNPC) by integrating the Toll-like receptor 9 (TLR9) agonist CpG with the FDA-approved ionizable lipid ALC-0315. This lipid nanoparticle (LNP) architecture establishes a safe, localized immunological depot that completely shields CpG from systemic nuclease degradation. Crucially, it enables the spatiotemporally coordinated co-delivery of physically admixed antigens and features a “smart” pH-responsive mechanism for targeted endosomal payload release. Consequently, LNPC efficiently activates the TLR9/MyD88 signaling pathway, promotes robust dendritic cell maturation, and drives a pronounced Th1-biased polarization. It uniquely induces the massive expansion of polyfunctional CD8+ T cells across diverse immunogens. In aggressive B16F10-OVA melanoma and HPV-associated TC-1 tumor models, LNPC-adjuvanted vaccines successfully remodeled the highly suppressive TME, achieving near-complete tumor clearance, significantly prolonged survival, and durable immune memory without inducing off-target systemic toxicity. Ultimately, the LNPC system represents a versatile, highly effective adjuvant platform with substantial clinical translational potential, offering a compelling new strategy for personalized tumor immunotherapy.
Similar content being viewed by others
Acknowledgements
We acknowledge the financial support from the National Key Research and Development Program of China (2024YFC2310401, S.W.L.), National Natural Science Foundation of China (Grant No. 82473313 to S.W.L. and 82302062 to L.Z.Z.), Xiamen Industry-Academia-Research Projects (2024CXY0113, Y.G.), the Natural Science Foundation of Xiamen, China (3502Z20227165, H.Y.), Xiang An Innovation Laboratory Science and Technology Plan Project (2023XAKJ0101019, L.Z.Z.), Supported by the Fundamental Research Funds for the Central Universities (20720220006 to N.S.X.).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
About this article
Cite this article
Zeng, Y., Xu, J., Han, F. et al. LNP-based delivery of a Toll-like receptor 9 agonist elicits potent adjuvant effects and antitumor immunity. npj Vaccines (2026). https://doi.org/10.1038/s41541-026-01465-1
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41541-026-01465-1
