Nano-NucleOTAC-mediated Z-DNA transformation disrupts mycobacterium tuberculosis biofilms and activates antibacterial immunity.
8 affiliations
- 1National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, China.
- 2National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, China. [email protected].
- 3The Affiliated Dongguan Songshan Lake Central Hospital, Guangdong Medical University, Dongguan, China.
- 4National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, China. [email protected].
- 5National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, China. [email protected].
- 6National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, China. [email protected].
- 7The Affiliated Dongguan Songshan Lake Central Hospital, Guangdong Medical University, Dongguan, China. [email protected].
- 8Guangdong Key Laboratory of Nanomedicine, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. [email protected].
Abstract
The biofilms of Mycobacterium Tuberculosis (Mtb) use extracellular DNA (eDNA) as a protective structural scaffold that shields resident bacteria from host immunity and antibiotics, promoting persistent infection. An FDA-approved DNase can partially hydrolyze eDNA but has limited affinity and nucleolytic activity against Z-form DNA (Z-DNA). After confirming the abundance of Z-DNA in Mtb biofilms, we develop Nano-NucleOTAC, a nano-nucleolysis targeting chimera that combines an eDNA-binding ligand (lactoferrin), a DNA intercalator (chloroquine) and DNase. Nano-NucleOTAC anchors to Z-DNA in Mtb H37Ra biofilms, enabling effective biofilm degradation via Z-DNA transformation and enzymatic cleavage. Following treatment, dispersed Mtb H37Ra clusters induce neutrophil extracellular trap (NET) formation and cytokine secretion (TNF, IL-1β, and IL-10) to recruit macrophages, while NET remodeling and nucleolysis enhance macrophage bactericidal effect vs. DNase alone. In mouse lung infection models, Nano-NucleOTAC improves lung drug retention, reduces pathology, and reactivates host immune responses. It also demonstrates high efficacy against Mtb strains of varying virulence (H37Ra, H37Rv) and non-tuberculous mycobacteria (Mycobacterium smegmatis). In clinical sputum samples, Nano-NucleOTAC potentiates rifampicin efficacy, and enhances neutrophil and macrophage antibacterial immunity in bronchoalveolar lavage fluid (BALF) and pus. This safe, versatile nucleic-acid-targeting strategy modulates bacterial biophysical barriers and host immunity to address biofilm-associated multidrug-resistant infections.
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BibTeX
@article{liu2026nanonucleotacmediated,
title = {{Nano-NucleOTAC-mediated Z-DNA transformation disrupts mycobacterium tuberculosis biofilms and activates antibacterial immunity.}},
author = {Deliang Liu and Pengfei Zhao and Yang Zhou and Zhuojun He and Zhiqiang Lin and Guiqin Dai and Senlin Shen and Yao Zhao and Pengqi Zhang and Yuying Chen and Dongcheng Ren and Jinzhi Pan and Xiafei Dai and Tetsuya Asakawa and Hongzhou Lu and Mingbin Zheng},
journal = {Nature communications},
year = {2026},
month = sep,
doi = {10.1038/s41467-026-77825-1},
url = {https://europepmc.org/article/MED/42897174},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Nano-NucleOTAC-mediated Z-DNA transformation disrupts mycobacterium tuberculosis biofilms and activates antibacterial immunity.
AU - Deliang Liu
AU - Pengfei Zhao
AU - Yang Zhou
AU - Zhuojun He
AU - Zhiqiang Lin
AU - Guiqin Dai
AU - Senlin Shen
AU - Yao Zhao
AU - Pengqi Zhang
AU - Yuying Chen
AU - Dongcheng Ren
AU - Jinzhi Pan
AU - Xiafei Dai
AU - Tetsuya Asakawa
AU - Hongzhou Lu
AU - Mingbin Zheng
PY - 2026
DA - 2026/09/17
JO - Nature communications
DO - 10.1038/s41467-026-77825-1
UR - https://europepmc.org/article/MED/42897174
AB - The biofilms of Mycobacterium Tuberculosis (Mtb) use extracellular DNA (eDNA) as a protective structural scaffold that shields resident bacteria from host immunity and antibiotics, promoting persistent infection. An FDA-approved DNase can partially hydrolyze eDNA but has limited affinity and nucleolytic activity against Z-form DNA (Z-DNA). After confirming the abundance of Z-DNA in Mtb biofilms, we develop Nano-NucleOTAC, a nano-nucleolysis targeting chimera that combines an eDNA-binding ligand (lactoferrin), a DNA intercalator (chloroquine) and DNase. Nano-NucleOTAC anchors to Z-DNA in Mtb H37Ra biofilms, enabling effective biofilm degradation via Z-DNA transformation and enzymatic cleavage. Following treatment, dispersed Mtb H37Ra clusters induce neutrophil extracellular trap (NET) formation and cytokine secretion (TNF, IL-1β, and IL-10) to recruit macrophages, while NET remodeling and nucleolysis enhance macrophage bactericidal effect vs. DNase alone. In mouse lung infection models, Nano-NucleOTAC improves lung drug retention, reduces pathology, and reactivates host immune responses. It also demonstrates high efficacy against Mtb strains of varying virulence (H37Ra, H37Rv) and non-tuberculous mycobacteria (Mycobacterium smegmatis). In clinical sputum samples, Nano-NucleOTAC potentiates rifampicin efficacy, and enhances neutrophil and macrophage antibacterial immunity in bronchoalveolar lavage fluid (BALF) and pus. This safe, versatile nucleic-acid-targeting strategy modulates bacterial biophysical barriers and host immunity to address biofilm-associated multidrug-resistant infections.
SN - 2041-1723
ER -