A dual-targeting lipid nanoparticle delivery system for precision phage therapy against multidrug-resistant Gram-negative bacteria
6 affiliations
- 1Cellular Signaling Laboratory, International Research Center for Sensory Biology and Technology of MOST, Key Laboratory of Molecular Biophysics of MOE, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, Hubei, China.
- 2School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Hongshan District, Wuhan 430074, Hubei, China.
- 3Department of Clinical Microbiology and Immunology, School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
- 4DWI-Leibniz Institute for Interactive Materials e.V., 52074 Aachen, Germany.
- 5Functional and Interactive Polymers, Institute of Technical and Macromolecular Chemistry, RWTH Aachen University, 52074 Aachen, Germany.
- 6Aachen Maastricht Institute for Biobased Materials (AMIBM), Maastricht University, Brightlands Chemelot Campus, 6167 RD Geleen, Netherlands.
Abstract
The escalating crisis of antimicrobial resistance, particularly among Gram-negative bacteria, demands innovative therapeutic strategies. Here, we present a dual-targeting lipid nanoparticle-chimeric phage (AbLCP) system engineered to combat multidrug-resistant (MDR) Gram-negative bacteria. Our design integrates a genetically modified M13 phage displaying anti-lipopolysaccharide (LPS) antibodies with polymyxin B conjugation, which is further encapsulated within anti-LPS antibody-functionalized lipid nanoparticles. This system overcomes the fundamental limitations of conventional phage therapy, enabling efficient cellular internalization, endosomal escape, and potent intracellular bactericidal activity. In murine models of Pseudomonas aeruginosa infection, AbLCP achieved superior bacterial clearance and up to 10³-fold reduction in bacterial burden at a 10³-fold lower effective dose than free polymyxin B, with 67-fold selective accumulation at infection sites, and attenuated systemic inflammation and preservation of gut microbiota. Mechanistically, AbLCP neutralized LPS to suppress inflammation and induced a lethal bacterial stress response. This work establishes a transformative nanophage platform that merges synthetic biology with nanomedicine, offering a promising strategy against MDR bacterial infections.
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BibTeX
@article{chen2026dualtargeting,
title = {{A dual-targeting lipid nanoparticle delivery system for precision phage therapy against multidrug-resistant Gram-negative bacteria}},
author = {Zhijun Chen and Wenjun Hu and Hui Nie and Yifan Zhang and Weilin Tang and Zhihe Yu and Jiajun Cao and Xunying Zhu and Xinrong Liu and Mingqian Chen and Udi Qimron and Andrij Pich and Huan Peng and Jianfeng Liu},
journal = {Science Advances},
year = {2026},
month = oct,
doi = {10.1126/sciadv.aeh7105},
url = {https://www.science.org/doi/abs/10.1126/sciadv.aeh7105},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - A dual-targeting lipid nanoparticle delivery system for precision phage therapy against multidrug-resistant Gram-negative bacteria
AU - Zhijun Chen
AU - Wenjun Hu
AU - Hui Nie
AU - Yifan Zhang
AU - Weilin Tang
AU - Zhihe Yu
AU - Jiajun Cao
AU - Xunying Zhu
AU - Xinrong Liu
AU - Mingqian Chen
AU - Udi Qimron
AU - Andrij Pich
AU - Huan Peng
AU - Jianfeng Liu
PY - 2026
DA - 2026/10/30
JO - Science Advances
DO - 10.1126/sciadv.aeh7105
UR - https://www.science.org/doi/abs/10.1126/sciadv.aeh7105
AB - The escalating crisis of antimicrobial resistance, particularly among Gram-negative bacteria, demands innovative therapeutic strategies. Here, we present a dual-targeting lipid nanoparticle-chimeric phage (AbLCP) system engineered to combat multidrug-resistant (MDR) Gram-negative bacteria. Our design integrates a genetically modified M13 phage displaying anti-lipopolysaccharide (LPS) antibodies with polymyxin B conjugation, which is further encapsulated within anti-LPS antibody-functionalized lipid nanoparticles. This system overcomes the fundamental limitations of conventional phage therapy, enabling efficient cellular internalization, endosomal escape, and potent intracellular bactericidal activity. In murine models of Pseudomonas aeruginosa infection, AbLCP achieved superior bacterial clearance and up to 10³-fold reduction in bacterial burden at a 10³-fold lower effective dose than free polymyxin B, with 67-fold selective accumulation at infection sites, and attenuated systemic inflammation and preservation of gut microbiota. Mechanistically, AbLCP neutralized LPS to suppress inflammation and induced a lethal bacterial stress response. This work establishes a transformative nanophage platform that merges synthetic biology with nanomedicine, offering a promising strategy against MDR bacterial infections.
SN - 2375-2548
ER -