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<p>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<sup>+</sup> 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.</p><p></p>

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LNP-based delivery of a Toll-like receptor 9 agonist elicits potent adjuvant effects and antitumor immunity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月9日

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  • Yarong Zeng,
  • Jialin Xu,
  • Feng Han,
  • Sibo Zhang,
  • Rong Su,
  • Yufang Li,
  • Renfei Gao,
  • Xiuli Zhang,
  • Lizhi Zhou,
  • Tingting Li,
  • Hai Yu,
  • Qingbing Zheng,
  • Ningshao Xia,
  • Shaowei Li,
  • Ying Gu

摘要

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.