Bio-Responsive Sliver Peroxide-Nanocarrier Serves as Broad-spectrum Metallo-β-lactamase Inhibitor for Combating Severe Pneumonia.

Metallo-β-lactamases (MBLs) represent a prevalent resistance mechanism in Gram-negative bacteria, rendering last-line carbapenem-related antibiotics ineffective. Here, a bio-responsive sliver peroxide (Ag 2 O 2 )-based nanovesicle, named Ag 2 O 2 @BP-MT@MM, was developed as a broad-spectrum MBL inhibitor for combating MBL-producing bacterial pneumonia. Ag 2 O 2 nanoparticle was first orderly modified with bovine serum albumin and polydopamine to co-load meropenem (MER) and [5-(p-fluorophenyl)-2-ureido]-thiophene-3-carboxamide (TPCA-1) and then encapsulated with macrophage membrane (MM) aimed to target inflammatory lung tissue specifically. The resultant Ag 2 O 2 @BP-MT@MM effectively abrogated MBL activity by displacing the Zn 2+ cofactor with Ag + in MBLs and displayed potent bactericidal and anti-inflammatory properties, specific targeting abilities, and great bio-responsive characteristics. After intravenous injection, the nanoparticles accumulated prominently at infection sites through MM-mediated targeting and acid-responsive drug release. Ag + released from Ag 2 O 2 decomposition at the infection sites effectively inhibited MBL activity and overcame the resistance of MBL-producing bacteria to MER, resulting in synergistic elimination of MBL-producing bacteria in conjunction with MER. In two murine infection models of NDM-1 + Klebsiella pneumoniae-induced severe pneumonia and NDM-1 + Escherichia coli-induced sepsis-related bacterial pneumonia, the nanoparticles significantly reduced bacterial loading, pro-inflammatory cytokine levels locally and systemically, and the recruitment and activation of neutrophils and macrophages. The modality also protected the lungs from severe injury. This innovative approach presents a promising new strategy for combating infections caused by MBL-producing carbapenem-resistant bacteria. This article is protected by copyright. All rights reserved.