Topology-Driven X-Shaped DNA as a cGAS Stimulator to Promote Dendritic Cell Activation and Antitumor Vaccine Efficacy.
- 1State Key Laboratory of Mechanism and Quality of Chinese Medicine, University of Macau, Macao SAR, China.
- 2Institute of Molecular Medicine (IMM), School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China.
Abstract
Vaccine adjuvants are essential for enhancing immune responses, yet the development of safe and potent adjuvants remains challenging. Here, we report a topology-guided nucleic acid adjuvant based on a four-way Holliday junction framework (X-DNA) designed to potentiate cGAS-STING signaling. In contrast to linear dsDNA, X-DNA presents a flexible, multibranched architecture that increases local DNA density and multivalent interaction potential, thereby favoring productive cGAS assembly. Molecular dynamics simulations demonstrate that X-DNA forms a more stable complex with cGAS and facilitates the establishment of the active 2:2 cGAS-DNA core assembly. Consistent with this mechanism, X-DNA markedly enhances cGAMP production and IFN-β secretion, promotes dendritic cell maturation and antigen presentation, and, when conjugated with antigenic peptides, strengthens antigen-specific CD8⁺ T-cell responses in vivo. In murine tumor models, X-DNA significantly improves the therapeutic efficacy of peptide vaccination and suppresses tumor progression. These findings identify DNA topology as a programmable determinant of cGAS activation and establish X-DNA as a structurally defined nucleic acid adjuvant for enhancing antitumor subunit vaccine efficacy.
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BibTeX
@article{li2026topologydriven,
title = {{Topology-Driven X-Shaped DNA as a cGAS Stimulator to Promote Dendritic Cell Activation and Antitumor Vaccine Efficacy.}},
author = {Jiabei Li and Xuan Wang and Dali Wei and Zhejie Chen and Ziyi Wang and Qing Yu and Yu Yang and Shengpeng Wang},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
year = {2026},
month = oct,
doi = {10.1002/advs.78563},
url = {https://europepmc.org/article/MED/42958766},
note = {CC BY},
}
RIS
TY - JOUR
TI - Topology-Driven X-Shaped DNA as a cGAS Stimulator to Promote Dendritic Cell Activation and Antitumor Vaccine Efficacy.
AU - Jiabei Li
AU - Xuan Wang
AU - Dali Wei
AU - Zhejie Chen
AU - Ziyi Wang
AU - Qing Yu
AU - Yu Yang
AU - Shengpeng Wang
PY - 2026
DA - 2026/10/29
JO - Advanced science (Weinheim, Baden-Wurttemberg, Germany)
DO - 10.1002/advs.78563
UR - https://europepmc.org/article/MED/42958766
AB - Vaccine adjuvants are essential for enhancing immune responses, yet the development of safe and potent adjuvants remains challenging. Here, we report a topology-guided nucleic acid adjuvant based on a four-way Holliday junction framework (X-DNA) designed to potentiate cGAS-STING signaling. In contrast to linear dsDNA, X-DNA presents a flexible, multibranched architecture that increases local DNA density and multivalent interaction potential, thereby favoring productive cGAS assembly. Molecular dynamics simulations demonstrate that X-DNA forms a more stable complex with cGAS and facilitates the establishment of the active 2:2 cGAS-DNA core assembly. Consistent with this mechanism, X-DNA markedly enhances cGAMP production and IFN-β secretion, promotes dendritic cell maturation and antigen presentation, and, when conjugated with antigenic peptides, strengthens antigen-specific CD8⁺ T-cell responses in vivo. In murine tumor models, X-DNA significantly improves the therapeutic efficacy of peptide vaccination and suppresses tumor progression. These findings identify DNA topology as a programmable determinant of cGAS activation and establish X-DNA as a structurally defined nucleic acid adjuvant for enhancing antitumor subunit vaccine efficacy.
SN - 2198-3844
ER -