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Here, a novel analog of the histone deacetylase inhibitor (HDACi), suberoylanilide hydroxamic acid (SAHA\u2010OH), was incorporated into immunomodulatory poly(lactic acid)\u2010based nanoparticles (iNP\u2010SAHA) by employing a prodrug approach through the covalent modification of poly(lactic\u2010co\u2010glycolic acid) (PLGA) with SAHA\u2010OH. iNP\u2010SAHA formulation allowed for controlled incorporation and delivery of SAHA\u2010OH from iNP\u2010SAHA and treatment led to multimodal biological responses including significant reductions in proinflammatory cytokine secretions and gene expression, while increasing the survival of primary macrophages under lipopolysaccharide (LPS) challenge. Using a lethal LPS\u2010induced endotoxemia mouse model of sepsis, iNP\u2010SAHA administration improved the survival of mice in a dose\u2010dependent manner and tended to improve survival at the lowest doses compared to iNP control. Further, iNP\u2010SAHA reduced the levels of plasma proinflammatory cytokines and chemokines associated with sepsis more significantly than iNP and similarly improved inflammation\u2010induced spleen and liver toxicity as iNP, supporting its potential polypharmacological activity. Collectively, iNP\u2010SAHA offers a potential drug delivery approach to modulate the multifaceted inflammatory responses observed in diseases such as sepsis.<\/jats:p>","DOI":"10.1002\/btm2.10611","type":"journal-article","created":{"date-parts":[[2023,10,14]],"date-time":"2023-10-14T04:35:25Z","timestamp":1697258125000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Multimodal nanoparticle\u2010containing modified suberoylanilide hydroxamic acid polymer conjugates to mitigate immune dysfunction in severe inflammation"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9562-1939","authenticated-orcid":false,"given":"Nhu","family":"Truong","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences University of Maryland School of Pharmacy  Baltimore Maryland 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