Localized NF‐κB Inhibition Reduces Lipid Nanoparticle‐Associated Inflammation

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.