Bio‐Responsive Sliver Peroxide‐Nanocarrier Serves as Broad‐Spectrum Metallo‐β‐lactamase Inhibitor for Combating Severe Pneumonia

Abstract

AbstractMetallo‐β‐lactamases (MBLs) represent a prevalent resistance mechanism in Gram‐negative bacteria, rendering last‐line carbapenem‐related antibiotics ineffective. Here, a bioresponsive sliver peroxide (Ag2O2)‐based nanovesicle, named Ag2O2@BP‐MT@MM, is developed as a broad‐spectrum MBL inhibitor for combating MBL‐producing bacterial pneumonia. Ag2O2 nanoparticle is 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 Ag2O2@BP‐MT@MM effectively abrogates MBL activity by displacing the Zn2+ cofactor in MBLs with Ag+ and displays potent bactericidal and anti‐inflammatory properties, specific targeting abilities, and great bioresponsive characteristics. After intravenous injection, the nanoparticles accumulate prominently at infection sites through MM‐mediated targeting . Ag+ released from Ag2O2 decomposition at the infection sites effectively inhibits MBL activity and overcomes the resistance of MBL‐producing bacteria to MER, resulting in synergistic elimination of 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 reduce bacterial loading, pro‐inflammatory cytokine levels locally and systemically, and the recruitment and activation of neutrophils and macrophages. This innovative approach presents a promising new strategy for combating infections caused by MBL‐producing carbapenem‐resistant bacteria.