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

  • Nat Commun. 2025 Dec 16;17(1):272. doi: 10.1038/s41467-025-66976-2.
Fangmin Chen  1  2 ,  Huijuan Zhang  1 ,  Shiqin Li  1 ,  Siyuan Ren  1  3 ,  Lujia Huang  1  2 ,  Yu Guo  1 ,  Yi Lai  1  2 ,  Zhixiong Cai  4 ,  Xiaolong Liu  4 ,  Zhiai Xu  5 ,  Haijun Yu  6  7  8  9
Affiliations
  • 1. State Key Laboratory of Chemical Biology & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 2. University of Chinese Academy of Sciences, Beijing, China.
  • 3. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.
  • 4. The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China.
  • 5. School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China. [email protected].
  • 6. State Key Laboratory of Chemical Biology & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 7. University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • 8. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China. [email protected].
  • 9. Yantai Key laboratory of Nanomedicine & Advanced Preparations, Yantai institute of Materia Medica, Yantai, Shandong, China. [email protected].
PMID: 41402324 DOI: 10.1038/s41467-025-66976-2
Abstract

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.

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