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LNP\u2010associated inflammation (LAI) manifests as\n                    <jats:italic>de novo<\/jats:italic>\n                    inflammation in select organs (e.g., in the lungs after inhalation) and severely worsens pre\u2010existing inflammation. NF\u2010\u03baB is a key transcription factor mediating this inflammation and represents a promising target for LAI mitigation strategies. However, systemic NF\u2010\u03baB inhibition carries risks of global immunosuppression, highlighting the need for localized inhibition. Here, we screen a panel of direct and indirect small molecule inhibitors of NF\u2010\u03baB for their ability to reduce LAI without disrupting LNPs\u2019 expression. We identify inhibitors that load efficiently into LNPs, retain anti\u2010inflammatory activity in vitro and in vivo, and preserve expression of cargo mRNA in target tissues. Our results demonstrate that co\u2010formulation of NF\u2010\u03baB inhibitors with cargo nucleic acids enables localized immunomodulation in LNPs, offering a modular strategy to enhance the safety profile of LNPs for therapeutic use in inflammatory or high\u2010risk patient populations.\n                  <\/jats:p>","DOI":"10.1002\/advs.202517931","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T19:33:00Z","timestamp":1774380780000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Localized NF\u2010\u03baB Inhibition Reduces Lipid Nanoparticle\u2010Associated Inflammation"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-0976-1955","authenticated-orcid":false,"given":"Carolann L.","family":"Espy","sequence":"first","affiliation":[{"name":"Department of Systems Pharmacology and Translational Therapeutics Perelman School of Medicine University 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