A Single-dose Vaccine Using Ultrasound-responsive Hydrogel for Controlled Antigen Release and Enhanced Immunization Efficacy

Zhi-Yuan Shi; Xing-Hui Si; Ren-Ming Wan; Zhen-Yi Zhu; Wan-Tong Song; Xue-Si Chen

doi:10.1007/s10118-025-3397-4

Your Location：

Home >

Browse articles >

A Single-dose Vaccine Using Ultrasound-responsive Hydrogel for Controlled Antigen Release and Enhanced Immunization Efficacy

RESEARCH ARTICLE | Updated：2025-09-26

- A Single-dose Vaccine Using Ultrasound-responsive Hydrogel for Controlled Antigen Release and Enhanced Immunization Efficacy
- Chinese Journal of Polymer Science Vol. 43, Issue 10, Pages: 1814-1824(2025)
- Affiliations：
  
  a.School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei 230026, China
  b.State Key Laboratory of Polymer Science and Technology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China
  c.Harbin Institute of Technology Zhengzhou Research Institute Medical Health Research Institute, Zhengzhou 450000, China
- Author bio：
  
  sixinghui@hitzri.cn (X.H.S.)
  wtsong@ciac.ac.cn (W.T.S.)
- Funds：
- DOI：10.1007/s10118-025-3397-4
  CLC：
- Received：16 May 2025，
  
  Revised：2025-06-12，
  
  Accepted：15 June 2025，
  
  Online First：02 September 2025，
  
  Published：05 October 2025
- Accepted：
Scan QR Code
Shi, Z. Y.; Si, X. H.; Wan, R. M.; Zhu, Z. Y.; Song, W. T.; Chen, X. S. A single-dose vaccine using ultrasound-responsive hydrogel for controlled antigen release and enhanced immunization efficacy. Chinese J. Polym. Sci. 2025, 43, 1814–1824

Zhi-Yuan Shi, Xing-Hui Si, Ren-Ming Wan, et al. A Single-dose Vaccine Using Ultrasound-responsive Hydrogel for Controlled Antigen Release and Enhanced Immunization Efficacy[J]. Chinese Journal of Polymer Science, 2025, 43(10): 1814-1824.
Shi, Z. Y.; Si, X. H.; Wan, R. M.; Zhu, Z. Y.; Song, W. T.; Chen, X. S. A single-dose vaccine using ultrasound-responsive hydrogel for controlled antigen release and enhanced immunization efficacy. Chinese J. Polym. Sci. 2025, 43, 1814–1824 DOI： 10.1007/s10118-025-3397-4.

Zhi-Yuan Shi, Xing-Hui Si, Ren-Ming Wan, et al. A Single-dose Vaccine Using Ultrasound-responsive Hydrogel for Controlled Antigen Release and Enhanced Immunization Efficacy[J]. Chinese Journal of Polymer Science, 2025, 43(10): 1814-1824. DOI： 10.1007/s10118-025-3397-4.

摘要

In order to achieve controlled multiple boosts of antigen release

we mix

ed 4-arm PEG-Se-Se-ONH

ODEX and 4-arm PEG-ONH

to prepare ultrasound-responsive hydrogel (URH) and successfully realized ultrasonic responsive release. URH is capable of sustaining antigen release under physiological conditions and can further boost antigen release upon ultrasound triggering. Due to the optimization of the release mode

the level of humoral immunity was highly enhanced.

Abstract

Sustained antigen release from delivery systems is a pivotal strategy to enhance vaccine-induced immune responses

primarily by mimicking the antigen exposure kinetics of natural infections to synchronously boost humoral and cellular immunity. However

the absence of an "antigen boost" effect in current approaches stands as a critical bottleneck

limiting the intensity and durability of immune responses. To address the critical gap of insufficient antigen boosting in sustained-release vaccine platforms

we engineered an ultrasound-responsive hydrogel (URH) with diselenide-functionalized 4-arm PEG-ONH

(4-arm PEG-Se-Se-ONH

)

4-arm PEG-ONH

and ODEX. Leveraging its exceptional ultrasonic sensitivity

the URH enables timely controlled

multiple-boost antigen release both

in vitro

and

in vivo

overcoming the limitations of conventional sustained-release systems. With the multiple boost release mode triggered by ultrasound

the immune response in lymph nodes was significantly stronger than that in sustained release group without ultrasonic trigger. At the same time

it also greatly improved the humoral immunity level

URH+US-OVA elicited 7.5×10

-fold higher anti-OVA Ig

titers over commercial Al-OVA vaccines and 440-fold higher than URH-OVA vaccines at day 40 post-vaccination

while the levels of blood routine and inflammatory factors were within the normal range

which proved that the safety of URH vaccines. The results support that the antigen release mode is a key factor affecting the immunological efficacy of vaccines

and URH can be modularized to regulate the multiple boost antigen release mode.

关键词

Keywords

references

Fauci, A. S.; Lane, H. C.; Redfield, R. R. Covid-19-navigating the uncharted. N. Engl. J. Med. 2020 , 382 , 1268−1269..

Leong, K. Y.; Tham, S. K.; Poh, C. L. Revolutionizing immunization: a comprehensive review of mRNA vaccine technology and applications. Virol. J. 2025 , 22 , 71..

Msemburi, W.; Karlinsky, A.; Knutson, V.; Aleshin-Guendel, S.; Chatterji, S.; Wakefield, J. The WHO estimates of excess mortality associated with the COVID-19 pandemic. Nature 2023 , 613 , 130−137.

Alablani, I. A. L.; Alenazi, M. J. F. COVID-ConvNet: a convolutional neural network classifier for diagnosing COVID-19 infection. Diagnostics 2023 , 13 , 1675..

Ji, G.; Zhang, Y.; Si, X.; Yao, H.; Ma, S.; Xu, Y.; Zhao, J.; Ma, C.; He, C.; Tang, Z.; Fang, X.; Song, W.; Chen, X. Biopolymer immune implants' sequential activation of innate and adaptive immunity for colorectal cancer postoperative immunotherapy. Adv. Mater. 2021 , 33 , 2004559..

Shi, Z. Y.; Gao, Z. H.; Zhuang, X. Y.; Si, X. H.; Huang, Z. C.; Di, Y. X.; Ma, S.; Guo, Z. P.; Li, C.; Jin, N. Y.; Huang, L. F.; Tian, M. Y.; Song, W. T.; Chen, X. S. Dynamic covalent hydrogel as a single-dose vaccine adjuvant for sustained antigen release and significantly elevated humoral immunity. Adv. Healthc. Mater. 2024 , 13 , 2400886..

Si, X.; Ji, G.; Ma, S.; Chen, H.; Shi, Z.; Zhang, Y.; Tang, Z.; Song, W.; Chen, X. Comprehensive evaluation of biopolymer immune implants for peritoneal metastasis carcinoma therapy. J. Control. Release 2023 , 353 , 289−302..

Ma, H.; He, C.; Chen, X. Injectable hydrogels as local depots at tumor sites for antitumor immunotherapy and immune-based combination therapy. Macromol. Biosci. 2021 , 21 , 2100039..

Si, X.; Song, W.; Chen, X. Polymeric drug delivery materials for cancer immunotherapy. Acta Polymerica Sinica (in Chinese) 2023 , 54 , 837−852..

Chen, J.; Wang, B.; Caserto, J. S.; Shariati, K.; Cao, P.; Pan, Y.; Xu, Q.; Ma, M. Sustained delivery of SARS-CoV-2 RBD subunit vaccine using a high affinity injectable hydrogel scaffold. Adv. Healthc. Mater. 2022 , 11 , 2101714..

Zhang, T.; He, P.; Guo, D. J.; Chen, K. X.; Hu, Z. Y.; Zou, Y. N. Research progress of aluminum phosphate adjuvants and their action mechanisms. Pharmaceutics 2023 , 15 , 1756..

Gao, Y. X.; Zhao, H. Q.; Zhao, J. Y.; Ma, S.; Si, X. H.; Liu, L. P.; Qiao, R. R.; Song, W. T.; Chen, X. S. Polymer-based synthetic oncolytic virus-like nanoparticles for cancer immunotherapy. Sci. China Chem. 2023 , 66 , 3506−3510..

Lee, J.; Jung, W.; Lee, D.; Kang, M.; Chung, H. J.; Yeom, J. Chirality-controlled lipid nanoparticles for mRNA delivery. ACS Appl. Mater. Interfaces 2025 , 17 , 18150−18159..

[Jang, E.; Lee, Y.; Ko, E.; Jeong, M.; Chang, J.; Lee, H. Development of lipid nanoparticle formulation for intramuscular administration of mRNA vaccine against respiratory syncytial virus. J. Pharm. Invest . 2025 , DOI: 10.1007/s40005-024-00719-1..

Zhu, Z.; Song, W.; Chen, X. Polymeric immune adjuvant materials. Acta Polymerica Sinica (in Chinese) 2023 , 54 , 534−549..

He, X.; Li, G. H.; Huang, L. T.; Shi, H. X.; Zhong, S.; Zhao, S. Y.; Jiao, X. Y.; Xin, J. X.; Yin, X. L.; Liu, S. B.; He, Z. S.; Guo, M. R.; Yang, C. L.; Jin, Z. H.; Guo, J.; Song, X. R. Nonviral targeted mRNA delivery: principles, progresses, and challenges. MedComm 2025 , 6 , e70035..

Irvine, D. J.; Aung, A.; Silva, M. Controlling timing and location in vaccines. Adv. Drug Deliver. Rev. 2020 , 158 , 91−115..

Wang, J.; Wang, S.; Ye, T.; Li, F.; Gao, X.; Wang, Y.; Ye, P.; Qing, S.; Wang, C.; Yue, H.; Wu, J.; Wei, W.; Ma, G. Choice of nanovaccine delivery mode has profound impacts on the intralymph node spatiotemporal distribution and immunotherapy efficacy. Adv. Sci. 2020 , 7 , 2001108..

Cirelli, K. M.; Carnathan, D. G.; Nogal, B.; Martin, J. T.; Rodriguez, O. L.; Upadhyay, A. A.; Enemuo, C. A.; Gebru, E. H.; Choe, Y.; Viviano, F.; Nakao, C.; Pauthner, M. G.; Reiss, S.; Cottrell, C. A.; Smith, M. L.; Bastidas, R.; Gibson, W.; Wolabaugh, A. N.; Melo, M. B.; Cossette, B.; Kumar, V.; Patel, N. B.; Tokatlian, T.; Menis, S.; Kulp, D. W.; Burton, D. R.; Murrell, B.; Schief, W. R.; Bosinger, S. E.; Ward, A. B.; Watson, C. T.; Silvestri, G.; Irvine, D. J.; Crotty, S. Slow delivery immunization enhances HIV neutralizing antibody and germinal center responses via modulation of immunodominance. Cell 2020 , 180 , 206−206..

Fan, M.; Jia, L.; Pang, M.; Yang, X.; Yang, Y.; Kamel Elyzayati, S.; Liao, Y.; Wang, H.; Zhu, Y.; Wang, Q. Injectable adhesive hydrogel as photothermal-derived antigen reservoir for enhanced anti-tumor immune. Adv. Funct. Mater. 2021 , 31 , 2010587..

Hao, H.; Wu, S.; Lin, J.; Zheng, Z.; Zhou, Y.; Zhang, Y.; Guo, Q.; Tian, F.; Zhao, M.; Chen, Y.; Xu, X.; Hou, L.; Wang, X.; Tang, R. Immunization against Zika by entrapping live virus in a subcutaneous self-adjuvanting hydrogel. Nat. Biomed. Eng. 2023 , 7 , 928..

Shi, P. J.; Zhang, X. K.; Cui, S.; Sun, L. J.; Liu, X.; Wang, B.; Zhang, Q. pH-Controlled DNA switching circuits with multi-state responsiveness for logic computation and control. Chem. Eur. J . 2025 , 31 , e202404541..

Kitayama, Y.; Shiba, H.; Harada, A. Temperature and pH dual-responsive polymer capsules prepared by interfacial photo-cross-linking with polymers comprising 6-(acryloyloxymethyl)uracil. ACS Appl. Polym. Mater. 2025 , 7 , 968−977..

Solanki, R.; Bhatia, D. Stimulus-responsive hydrogels for targeted cancer therapy. Gels 2024 , 10 , 440..

Peng, C.;Zhu, Y. L.; Zhang, K. B.; Wang, Y. W.; Zheng, Y.; Liu, Y.; Fu, W. L.; Tan, H.; Fu, Q.; Ding, M. M. Redox-switchable multicolor luminescent polymers for theragnosis of osteoarthritis. Nat. Commun. 2024 , 15 , 10078..

Hu, Z. C.; Zhou, X.; Zhang, W.; Zhang, L. Y.; Li, L.; Gao, Y.; Wang, C. G. Photothermal amplified multizyme activity for synergistic photothermal-catalytic tumor therapy. J. Colloid Interface Sci. 2025 , 679 , 375−383..

Lee, T. M.; Su, S. F.; Chou, T. F.; Lee, Y. T.; Tsai, C. H. Loss of preconditioning by attenuated activation of myocardial ATP-sensitive potassium channels in elderly patients undergoing coronary angioplasty. Circulation 2002 , 105 , 334−340..

He, M. Y.; Wang, Y. H.; Li, D. Z.; Zhang, M. Y.; Wang, T.; Zhi, F.; Ji, X. Y.; Ding, D. W. Recent applications of phase-change materials in tumor therapy and theranostics. Bio. Adv. 2023 , 147 , 213309..

Cai, Z. H.; Yang, Z. K.; Wang, Y.; Li, Y.; Zhao, H.; Zhao, H. W.; Yang, X.; Wang, C.; Meng, T. T.; Tong, X.; Zheng, H.; He, Z. Y.; Niu, C. L.; Yang, J. Z.; Chen, F.; Yang, Z.; Zou, Z. G.; Li, W. B. Tumor treating induced fields: a new treatment option for patients with glioblastoma. Front. Neurol. 2024 , 15 , 1413236..

Chauke, N. M.; Mohlala, R. L.; Ngqoloda, S.; Raphulu, M. C. Harnessing visible light: enhancing TiO 2 photocatalysis with photosensitizers for sustainable and efficient environmental solutions. Front. Chem. Eng. 2024 , 6 , 1356021..

Han, Y. Y.; Liu, C.; Yin, S.; Cui, J.; Sun, Y.; Xue, B.; Jiang, C. P.; Gu, X. S.; Qin, M.; Wang, W.; Xu, H. P.; Cao, Y. Dynamic diselenide hydrogels for controlled tumor organoid culture and dendritic cell vaccination. ACS Appl. Mater. Interfaces 2024 , 16 , 69114−69124..

Kong, C. Y.; Li, Y. R.; Xu, Y. J.; Luo, C. W.; Shen, N.; Tang, Z. H.; Chen, X. S. Ultrasound irradiation-induced superoxid e anion radical mediates the reduction of tetravalent platinum prodrug for antitumor therapy. CCS Chem. 2024 , 7 , 1142−1156..

Ma, X. T.; Yao, M. N.; Shi, J. Y.; Li, X. D.; Gao, Y.; Luo, Q.; Hou, R.; Liang, X. L.; Wang, F. High intensity focused ultrasound-responsive and ultrastable cerasomal perfluorocarbon nanodroplets for alleviating tumor multidrug resistance and epithelial-mesenchymal transition. ACS Nano 2020 , 14 , 15904−15918..

Wang, X. J.; Kim, G.; Chu, J. L.; Song, T. J.; Yang, Z. L.; Guo, W. J.; Shao, X. L.; Oelze, M. L.; Li, K. C.; Lu, Y. Noninvasive and spatiotemporal control of DNAzyme-based imaging of metal ions in vivo using high-intensity focused ultrasound. J. Am. Chem. Soc. 2022 , 144 , 5812−5819..

Liu, Z.; Gao, S. J.; Zhao, Y.; Li, P. J.; Liu, J.; Li, P.; Tan, K. B.; Xie, F. Disruption of tumor neovasculature by microbubble enhanced ultrasound: a potentiao new physical therapy of anti-angiogenesis. Ultrasound Med. Biol. 2012 , 38 , 253−261..

Tan, Y. Z.; Xu, H. P. Selenium-containing dynamic materials: structure programming through selective dissipation. Acc. Mater. Res. 2024 , 5 , 739−751..

Watson, K. D.; Lai, C. Y.; Qin, S.; Kruse, D. E.; Lin, Y. C.; Seo, J. W.; Cardiff, R. D.; Mahakian, L. M.; Beegle,J.; Inghanm, E. S.; Curry, F. R.; Reed, R. K.; Ferrara, K. W. Ultrasound increases nanoparticle delivery by reducing intratumoral pressure and increasing transport in epithelial and epithelial-mesenchymal transition tumors. Cancer Res. 2012 , 72 , 1485−1493..

Lammertink, B. H. A.; Bos, C.; van der Wurff-Jacobs, K. M.; Storm, G.; Moonen, C. T.; Deckers, R. Increase of intracellular cisplatin levels and radiosensitization by ultrasound in combination with microbubbles. J. Control. Release 2016 , 238 , 157−165..

Zhou, Y.; Huo, S. D.; Loznik, M.; Göstl, R.; Boersma, A. J.; Herrmann, A. Controlling optical and catalytic activity of genetically engineered proteins by ultrasound. Angew. Chem. Int. Ed. 2021 , 60 , 1493−1497..

Boopathy, A. V.; Mandal, A.; Kulp, D. W.; Menis, S.; Bennett, N. R.; Watkins, H. C.; Wang, W.; Martin, J. T.; Thai, N. T.; He, Y.; Schief, W. R.; Hammond, P. T.; Irvine, D. J. Enhancing humoral immunity via sustained-release implantable microneedle patch vaccination. PNAS 2019 , 116 , 16473−16478..

Zhou, X. Y.; Wang, H. Z.; Luo, Y.; Cui, L.; Guan, Y.; Zhang, Y. J. Single-injection COVID-19 subunit vaccine elicits potent immune responses. Acta Bio. 2022 , 151 , 491−500..

Si, X. H.; Ji, G. F.; Ma, S.; Liu, L. P.; Zhu, Z. Y.; Zhang, Y.; Tang, Z. H.; Song, W. T.; Chen, X. S. Safety evaluation of biopolymer immune implants in rats and rabbits as well as therapeutic effects on gastric cancer peritoneal metastasis carcinoma. Sci. China Mater. 2024 , 67 , 2080−2089..

Huang, Z.; Zhuang, X.; Liu, L.; Zhao, J.; Ma, S.; Si, X.; Zhu, Z.; Wu, F.; Jin, N.; Tian, M.; Song, W.; Chen, X. Modularized viromimetic polymer nanoparticle vaccines (VPNVaxs) to elicit durable and effective humoral immune responses. Natl. Sci. Rev. 2024 , 11 , nwad310..

Views

429

Downloads

CSCD

Alert me when the article has been cited

Submit

Tools

Publicity Resources

Green Fabrication of High-strength Silk Fibroin Hydrogels via Thermal Oscillation in All-aqueous Media

Polyoxometalate-doped Chitosan Quaternary Ammonium/Polyacrylamide Interpenetrating Hydrogels with Enhanced Mechanical and Tribological Properties

Direct Ink Writing 3D Printing of Hydrogel Bioelectronics

Anti-biofouling Hydrogels: Surface Hydration, Classification, and Biomedical Applications

Enhancing Processability of Phenylethynyl-terminated Imide Oligomers and Properties of Cured Polyimides via ―CF3 Incorporation

Related Author

Yu-Si Long

Mei-Yi Lu

Jia-Wei Qi

Geng Chen

Yu Sun

Xiu-Xia He

Tian-Hui Zhang

Li-Guo Cui

Related Institution

State Key Laboratory of Integrated Optoelectronics, Key Laboratory of UV Light-Emitting Materials and Technology of Ministry of Education, School of Physics, Northeast Normal University

School of Life Science and Technology, Changchun University of Science and Technology

Changchun SinoBiomaterials Co., Ltd.

State Key Laboratory of Solid Lubrication, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences

College of Chemistry and Chemical Engineering, Lanzhou University

⁰