Nanovaccines co-delivering antigen and dual TLR agonists potentiate aged immunity by orchestrating TCR repertoire.

Authors

Haolin Chen, Zhihui Zhang, Zhenfu Wen, Zeyu Yang, Liyan Li, Sheng Wang, Qiang Gao, Hong Liu, Lixin Liu, Yongming Chen

Published in

Journal of controlled release : official journal of the Controlled Release Society. Pages 115262. Aug 13, 2026. Epub Aug 13, 2026.

Abstract

Immunosenescence increases susceptibility to varicella-zoster virus (VZV) infection in the elderly while compromising vaccine responsiveness. Although clinical adjuvants such as AS01 have improved vaccine efficacy, challenges associated with saponin-based components and separate antigen-adjuvant formulations persist. Here, we developed a nanovaccine, NP(gEIM), that co-encapsulates VZV glycoprotein E (gE) with the TLR4 agonist MPLA and TLR7/8 agonist IMQ in lipid nanoparticles via flash nanocomplexation (FNC), enabling coordinated co-delivery of antigen and adjuvants. NP(gEIM) efficiently targeted draining lymph nodes and promoted antigen-presenting cell uptake and maturation. In young and aged mice, NP(gEIM) elicited gE-specific antibody responses and Th1-biased cellular immunity comparable to AS01-adjuvanted gE vaccines while exceeding aluminum-adjuvanted vaccines. Moreover, NP(gEIM) enhanced IFN-γ and TNF-α production by antigen-specific CD4⁺ and CD8⁺ T cells while reducing immunosuppressive Treg and MDSC populations in aged mice. Notably, NP(gEIM) reshaped the TCR repertoire by promoting selective expansion of putative antigen-responsive T cell clones and altering TCR V/J gene usage and CDR3 length distribution, providing molecular insights into vaccine-induced T cell responses. Collectively, this study presents a nanovaccine strategy enabling coordinated delivery of antigen and dual TLR agonists. By integrating humoral and cellular immunity with TCR repertoire modulation, NP(gEIM) offers a potential strategy for improving vaccine responses in aging populations and developing vaccines against age-associated infectious diseases.

PMID:
42595179
Bibliographic data and abstract were imported from PubMed on 14 Aug 2026.

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