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<p>The effective treatment of bacterial infections requires rapid and selective enrichment of antibacterial agents on bacterial surfaces within infectious microenvironments. Transition metal ion-based antibacterial agents show broad-spectrum bactericidal activity, but they usually rely on passive diffusion and stochastic bacterial contact, limiting their ability to establish sufficient local doses within short treatment windows. Herein, an M13 phage-mediated targeting strategy was developed for the rapid enrichment and delivery of copper ion–protocatechuic acid nanoparticles (CP NPs). Through phage display, an M13 phage targeting methicillin-resistant <i>Staphylococcus aureus</i> (<i>MRSA</i>-targeting phage, MTP) and an M13 phage targeting <i>Pseudomonas aeruginosa</i> (<i>P. aeruginosa</i>-targeting phage, PTP) were identified. MTP and PTP retained the typical filamentous morphology of M13 phage and selectively adhered to corresponding bacteria within 1&#xa0;min. Protocatechuic acid (PCA) was then used as a polyphenolic bridge for phage-surface adhesion and Cu<sup>2+</sup> coordination, yielding CP@MTP and CP@PTP, which integrate bacterial recognition, metal–polyphenol assembly, and copper-based antibacterial activity into filamentous delivery scaffolds. After only 10&#xa0;min of bacterial exposure, CP@MTP selectively reduced <i>MRSA</i> by 3 log, while CP@PTP reduced <i>P. aeruginosa</i> by 1.7 log, likely owing to rapid phage-mediated CP NP enrichment on bacterial surfaces. Transcriptomic analysis further revealed bacterial stress responses induced by targeted copper delivery. In zebrafish larval tail-fin infection models, CP@MTP and CP@PTP effectively eradicated corresponding bacteria and reduced neutrophil recruitment. In a murine <i>P. aeruginosa</i> pneumonia model, CP@PTP prolonged lung retention, reduced pulmonary bacterial burden, and alleviated inflammatory lung injury. This study establishes targeted M13 phages as spatial regulators for rapid and precision antibacterial therapy.</p> Graphical abstract <p></p>

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Phage-guided rapid enrichment of copper-protocatechuic acid nanoparticles for targeted antibacterial therapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月9日

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  • Fang Liu,
  • Haojie Chen,
  • Yue Huang,
  • Yongcheng Chen,
  • Shiya Wang,
  • Jian Ji,
  • Qiao Jin

摘要

The effective treatment of bacterial infections requires rapid and selective enrichment of antibacterial agents on bacterial surfaces within infectious microenvironments. Transition metal ion-based antibacterial agents show broad-spectrum bactericidal activity, but they usually rely on passive diffusion and stochastic bacterial contact, limiting their ability to establish sufficient local doses within short treatment windows. Herein, an M13 phage-mediated targeting strategy was developed for the rapid enrichment and delivery of copper ion–protocatechuic acid nanoparticles (CP NPs). Through phage display, an M13 phage targeting methicillin-resistant Staphylococcus aureus (MRSA-targeting phage, MTP) and an M13 phage targeting Pseudomonas aeruginosa (P. aeruginosa-targeting phage, PTP) were identified. MTP and PTP retained the typical filamentous morphology of M13 phage and selectively adhered to corresponding bacteria within 1 min. Protocatechuic acid (PCA) was then used as a polyphenolic bridge for phage-surface adhesion and Cu2+ coordination, yielding CP@MTP and CP@PTP, which integrate bacterial recognition, metal–polyphenol assembly, and copper-based antibacterial activity into filamentous delivery scaffolds. After only 10 min of bacterial exposure, CP@MTP selectively reduced MRSA by 3 log, while CP@PTP reduced P. aeruginosa by 1.7 log, likely owing to rapid phage-mediated CP NP enrichment on bacterial surfaces. Transcriptomic analysis further revealed bacterial stress responses induced by targeted copper delivery. In zebrafish larval tail-fin infection models, CP@MTP and CP@PTP effectively eradicated corresponding bacteria and reduced neutrophil recruitment. In a murine P. aeruginosa pneumonia model, CP@PTP prolonged lung retention, reduced pulmonary bacterial burden, and alleviated inflammatory lung injury. This study establishes targeted M13 phages as spatial regulators for rapid and precision antibacterial therapy.

Graphical abstract