Language
English
Publication Date
6-1-2026
Journal
Advanced Science
DOI
10.1002/advs.202517931
PMID
41875360
PMCID
PMC13587984
PubMedCentral® Posted Date
3-24-2026
PubMedCentral® Full Text Version
Post-print
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.
Keywords
NF-kappa B, Animals, Nanoparticles, Inflammation, Mice, Lipids, Humans, Anti-Inflammatory Agents, Liposomes, inflammation, nanoparticles, NF‐κB inhibition, small molecule drug loading
Published Open-Access
yes
Recommended Citation
Espy, Carolann L; Wu, Jichuan; Omo-Lamai, Serena; et al., "Localized NF-κB Inhibition Reduces Lipid Nanoparticle-Associated Inflammation" (2026). Faculty, Staff and Students Publications. 8613.
https://digitalcommons.library.tmc.edu/baylor_docs/8613