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<p>Spatiotemporally-controllable regulation of innate immunity in lymph node remains a critical challenge to implement effective cancer vaccination. Here we report an ultrasound-activatable strategy to precisely stimulate innate immunity activation in vivo. Mechanistically, ultrasound-triggered mechanical and oxidative forces synchronously activate innate immune pathways in antigen-presenting cells via calcium ion influx and mitochondria DNA release. We next design a polypeptide sono-adjuvant (SONA) library with adjustable physicochemical properties for lymph node-targeting delivery. The top-performed SONA specifically activates robust and durable innate immune responses in lymph node upon localized ultrasound stimulation. The combination of SONA-based vaccine with ultrasound stimulation induces about 3.0-fold higher antigen-specific T cell responses than conventional adjuvant-based vaccines. Moreover, in syngeneic mouse models of orthotopic breast and liver tumors, the combination of SONA-based neoantigen vaccine with ultrasound stimulation markedly boosts immune checkpoint blockade therapy to suppress tumor growth and distant metastasis. Collectively, the polypeptide sono-adjuvant offers great promise for precise regulation of innate immunity and cancer vaccine therapy.</p>

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Polypeptide sono-adjuvant for ultrasound-activatable regulation of innate immunity and cancer vaccination therapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月16日

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  • Fangmin Chen,
  • Huijuan Zhang,
  • Shiqin Li,
  • Siyuan Ren,
  • Lujia Huang,
  • Yu Guo,
  • Yi Lai,
  • Zhixiong Cai,
  • Xiaolong Liu,
  • Zhiai Xu,
  • Haijun Yu

摘要

Spatiotemporally-controllable regulation of innate immunity in lymph node remains a critical challenge to implement effective cancer vaccination. Here we report an ultrasound-activatable strategy to precisely stimulate innate immunity activation in vivo. Mechanistically, ultrasound-triggered mechanical and oxidative forces synchronously activate innate immune pathways in antigen-presenting cells via calcium ion influx and mitochondria DNA release. We next design a polypeptide sono-adjuvant (SONA) library with adjustable physicochemical properties for lymph node-targeting delivery. The top-performed SONA specifically activates robust and durable innate immune responses in lymph node upon localized ultrasound stimulation. The combination of SONA-based vaccine with ultrasound stimulation induces about 3.0-fold higher antigen-specific T cell responses than conventional adjuvant-based vaccines. Moreover, in syngeneic mouse models of orthotopic breast and liver tumors, the combination of SONA-based neoantigen vaccine with ultrasound stimulation markedly boosts immune checkpoint blockade therapy to suppress tumor growth and distant metastasis. Collectively, the polypeptide sono-adjuvant offers great promise for precise regulation of innate immunity and cancer vaccine therapy.