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The presence of bacterial polysaccharides that impede the penetration of many antimicrobials and protect them from the innate immune system contributes to resistance and pathogenicity. No currently approved antibiotics target the polysaccharide regions of microbes. Here, describe monolaurin\u2010based niosomes, the first lipid nanoparticles that can eliminate bacterial polysaccharides from hypervirulent <jats:italic>Klebsiella pneumoniae<\/jats:italic>, are described. Their combination with polymyxin B shows no cytotoxicity <jats:italic>in vitro<\/jats:italic> and is highly effective in combating <jats:italic>K. pneumoniae<\/jats:italic> infection <jats:italic>in vivo<\/jats:italic>. Comprehensive mechanistic studies have revealed that antimicrobial activity proceeds via a multimodal mechanism. Initially, lipid nanoparticles disrupt polysaccharides, then outer and inner membranes are destabilized and destroyed by polymyxin B, resulting in synergistic cell lysis. This novel lipidic nanoparticle system shows tremendous promise as a highly effective antimicrobial treatment targeting multidrug\u2010resistant Gram\u2010negative pathogens.<\/jats:p>","DOI":"10.1002\/smll.202305052","type":"journal-article","created":{"date-parts":[[2023,10,6]],"date-time":"2023-10-06T17:31:58Z","timestamp":1696613518000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Polysaccharide\u2010Targeting Lipid Nanoparticles to Kill Gram\u2010Negative Bacteria"],"prefix":"10.1002","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2558-4415","authenticated-orcid":false,"given":"Xiangfeng","family":"Lai","sequence":"first","affiliation":[{"name":"Department of Materials Science and Engineering Faculty of Engineering Monash University  Clayton Victoria 3800 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seong 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