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

Abstract Metallo‐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.