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We previously demonstrated that diflunisal, a nonsteroidal anti\u2010inflammatory drug, decreases <jats:italic>S. aureus<\/jats:italic>\u2010induced bone destruction during osteomyelitis when delivered locally from a resorbable drug delivery depot. However, local diflunisal therapy was complicated by bacterial colonization of the depot's surface, highlighting a common pitfall of devices for local drug delivery to infected tissue. It is, therefore, critical to develop an alternative drug delivery method for diflunisal to successfully repurpose this drug as an antivirulence therapy for osteomyelitis. We hypothesized that a nanoparticle\u2010based parenteral delivery strategy would provide a method for delivering diflunisal to infected tissue while circumventing the complications associated with local delivery. In this study, we demonstrate that poly(propylene sulfide) (PPS) nanoparticles accumulate at the infectious focus in a murine model of staphylococcal osteomyelitis and are capable of efficaciously delivering diflunisal to infected bone. Moreover, diflunisal\u2010loaded PPS nanoparticles effectively decrease <jats:italic>S. aureus<\/jats:italic>\u2010mediated bone destruction, establishing the feasibility of systemic delivery of an antivirulence compound to mitigate bone pathology during osteomyelitis.<\/jats:p>","DOI":"10.1002\/jor.24948","type":"journal-article","created":{"date-parts":[[2020,12,10]],"date-time":"2020-12-10T23:03:27Z","timestamp":1607641407000},"page":"426-437","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Diflunisal\u2010loaded poly(propylene sulfide) nanoparticles decrease <i>S. aureus<\/i>\u2010mediated bone destruction during osteomyelitis"],"prefix":"10.1002","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3710-8037","authenticated-orcid":false,"given":"Caleb A.","family":"Ford","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering Vanderbilt University Nashville Tennessee 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