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Cited by 0Immunotherapy and Immune ResponsesChemical Synthesis and AnalysisCancer Immunotherapy and Biomarkers

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Linker-directed lipid-antigen conjugates co-enhance lymph node targeting and antigen presentation for potent T cell immunity

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Zhu, Junfei, Bai, Licheng, Wang, Chun, Liu, Jiating, Chen, Yuhua, Zhang, Wenxia, Weng, Jun, Wei, Lin, Wei, Zigong·2026·Materials Today Bio
DOI 10.1016/j.mtbio.2026.103505PMC PMC13452237
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Abstract

The clinical efficacy of peptide-based cancer vaccines is limited by inefficient lymphatic delivery and suboptimal antigen presentation. Here, we report a rationally engineered class of lipid-antigen conjugates that co-enhance lymph node (LN) targeting and antigen-presenting cell (APC) uptake through molecular-level structural optimization. By systematically varying lipid tail composition and linker chemistry, we identify a lead construct (dOA-K-O) incorporating a dioleic acid (dOA) lipid tail and an L-lysine (K) linker, which outperforms the clinically used DSPE-PEG 2000 conjugate (DSPE-O). Mechanistically, the positively charged L-lysine linker promotes albumin binding while reducing excessive self-assembly, enhancing lymphatic trafficking and facilitating APC internalization. In vivo , dOA-K-O elicits robust antigen cross-presentation and induces an 8-fold increase in antigen-specific CD8 + T cell responses compared to unmodified antigenic peptide and 3-fold higher than DSPE-O. This enhanced cellular immunity translates into marked tumor suppression in both prophylactic and therapeutic B16-OVA melanoma models. Our results establish a design paradigm in which linker chemistry and lipid tail composition are synergistically optimized to boost the immunogenicity of peptide vaccines for cancer immunotherapy, which may provide a chemical and structural basis for the optimization of peptide-based vaccine delivery systems.

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Metadata

Authors
Zhu, J., Bai, L., Wang, C., Liu, J., Chen, Y., Zhang, W., Weng, J., Wei, L., & Wei, Z.
Affiliations
State Key Laboratory of Biocatalysis and Enzyme Engineering (CN)
Corresponding author
  • Zhu, Junfei
  • Wei, Lin
  • Wei, Zigong
ORCID
Venue
Materials Today Bio
Publisher
Elsevier BV
Published
2026-08
Volume
39
Pages
103505
ISSN
2590-0064 (ISSN-L)
DOI
10.1016/j.mtbio.2026.103505
PMC
PMC13452237
OpenAlex
W7171548061
Cited by
0
References
4
FWCI
0.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Materials Today Bio (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
Funders
China Postdoctoral Science Foundation
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords
linker chemistry, lymph node targeting, antigen presentation, T cell immunity, peptide vaccine, cancer immunotherapy, melanoma, tumor suppression, vaccine delivery

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