Localized NF‐κB Inhibition Reduces Lipid Nanoparticle‐Associated Inflammation

ABSTRACT Lipid nanoparticles (LNPs) are widely used for nucleic acid delivery, yet their clinical utility is limited by an acute inflammatory response post‐administration. LNP‐associated inflammation (LAI) manifests as de novo inflammation in select organs (e.g., in the lungs after inhalation) and severely worsens pre‐existing inflammation. NF‐κB is a key transcription factor mediating this inflammation and represents a promising target for LAI mitigation strategies. However, systemic NF‐κB 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‐κB for their ability to reduce LAI without disrupting LNPs’ expression. We identify inhibitors that load efficiently into LNPs, retain anti‐inflammatory activity in vitro and in vivo, and preserve expression of cargo mRNA in target tissues. Our results demonstrate that co‐formulation of NF‐κB 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‐risk patient populations.