“Drug-Delivering-Drug” nanocomplexes reinforce cytosolic nucleic acid sensing for broad-spectrum antiviral activity in fish
- 1Key Laboratory of Fishery Drug Development, Ministry of Agriculture and Rural affairs, Guangdong Province Key Laboratory of Aquatic Animal Immunology Technology, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, 510380 China
- 2Hainan Fisheries Innovation Research Institute, Chinese Academy of Fishery Sciences, Sanya, 572018 China
- 3Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian, 116023 China
Abstract
Viral diseases pose a persistent global threat, necessitating next-generation antiviral strategies that overcome the limited antiviral spectrum, rapid resistance, and insufficient immune engagement of conventional therapeutics. Herein, a carrier-free, “drug-delivering-drug” antiviral nanocomplex, termed BBTS25, is developed through directed self-assembly of baicalin and the bioactive peptide TS25. BBTS25 exhibits potent broad-spectrum antiviral efficacy. Notably, in a representative viral model, it strongly suppresses viral replication, reducing intracellular and supernatant viral loads by approximately 70% and 80%, respectively, while concurrently compromising virion structural integrity. Mechanistically, atomistic molecular dynamics simulations reveal that BBTS25 efficiently penetrates cellular membranes, with its peptide component forming strong interactions with intracellular nucleic acids. The interaction shields nucleic acids from nuclease-mediated degradation, thereby sustaining the activation of the type I interferon pathway. Consistently, transcriptomic profiling of treated cells shows robust induction of interferon-stimulated gene networks and activation of innate antiviral responses. In vivo, BBTS25 administration in a lower vertebrate (teleost) model enhances survival by approximately 47% and demonstrates excellent biocompatibility. Furthermore, spleen transcriptomic analysis and quantitative PCR indicate that BBTS25 activates dendritic cells and macrophages, and promotes type I interferon-associated immune responses. This work establishes a broadly applicable strategy for next-generation host-directed antiviral intervention via self-assembly of poorly soluble natural compounds and unstable bioactive peptides.
Graphical Abstract:
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12951-026-04750-2.
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BibTeX
@article{ma2026drugdeliveringdrug,
title = {{“Drug-Delivering-Drug” nanocomplexes reinforce cytosolic nucleic acid sensing for broad-spectrum antiviral activity in fish}},
author = {Baofu Ma and Wenjuan Yao and Xiaozhe Fu and Yinjie Niu and Ouqin Chang and Kaiguang Yang and Hongru Liang and Xia Luo and Wenwen Xiao and Qiang Lin and Ningqiu Li},
journal = {Journal of Nanobiotechnology},
year = {2026},
month = jun,
doi = {10.1186/s12951-026-04750-2},
url = {https://doi.org/10.1186/s12951-026-04750-2},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - “Drug-Delivering-Drug” nanocomplexes reinforce cytosolic nucleic acid sensing for broad-spectrum antiviral activity in fish
AU - Baofu Ma
AU - Wenjuan Yao
AU - Xiaozhe Fu
AU - Yinjie Niu
AU - Ouqin Chang
AU - Kaiguang Yang
AU - Hongru Liang
AU - Xia Luo
AU - Wenwen Xiao
AU - Qiang Lin
AU - Ningqiu Li
PY - 2026
DA - 2026/06/28
JO - Journal of Nanobiotechnology
DO - 10.1186/s12951-026-04750-2
UR - https://doi.org/10.1186/s12951-026-04750-2
AB - Viral diseases pose a persistent global threat, necessitating next-generation antiviral strategies that overcome the limited antiviral spectrum, rapid resistance, and insufficient immune engagement of conventional therapeutics. Herein, a carrier-free, “drug-delivering-drug” antiviral nanocomplex, termed BBTS25, is developed through directed self-assembly of baicalin and the bioactive peptide TS25. BBTS25 exhibits potent broad-spectrum antiviral efficacy. Notably, in a representative viral model, it strongly suppresses viral replication, reducing intracellular and supernatant viral loads by approximately 70% and 80%, respectively, while concurrently compromising virion structural integrity. Mechanistically, atomistic molecular dynamics simulations reveal that BBTS25 efficiently penetrates cellular membranes, with its peptide component forming strong interactions with intracellular nucleic acids. The interaction shields nucleic acids from nuclease-mediated degradation, thereby sustaining the activation of the type I interferon pathway. Consistently, transcriptomic profiling of treated cells shows robust induction of interferon-stimulated gene networks and activation of innate antiviral responses. In vivo, BBTS25 administration in a lower vertebrate (teleost) model enhances survival by approximately 47% and demonstrates excellent biocompatibility. Furthermore, spleen transcriptomic analysis and quantitative PCR indicate that BBTS25 activates dendritic cells and macrophages, and promotes type I interferon-associated immune responses. This work establishes a broadly applicable strategy for next-generation host-directed antiviral intervention via self-assembly of poorly soluble natural compounds and unstable bioactive peptides. Graphical Abstract: Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12951-026-04750-2.
SN - 1477-3155
ER -