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Journal article
Localized NF‐κB Inhibition Reduces Lipid Nanoparticle‐Associated Inflammation
Advanced science, e17931
24 Mar 2026
PMID: 41875360
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.
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Details
- Title
- Localized NF‐κB Inhibition Reduces Lipid Nanoparticle‐Associated Inflammation
- Creators
- Carolann L. Espy - University of PennsylvaniaJichuan Wu - University of PennsylvaniaSerena Omo-Lamai - University of PennsylvaniaLiuqian Wang - University of PennsylvaniaFengyi Dong - University of PennsylvaniaAleksa Milosavljevic - University of PennsylvaniaSarah O'Neill - University of PennsylvaniaTaylor Brysgel - University of PennsylvaniaYufei Wang - University of PennsylvaniaMichael Zaleski - University of PennsylvaniaEmily Wolfe - School of Biomedical Engineering Science and Health Systems Drexel University Philadelphia Pennsylvania USARhea Maheshwari - University of PennsylvaniaManthan Patel - University of PennsylvaniaDirk Trauner - University of PennsylvaniaJia Nong - Department of Systems Pharmacology and Translational Therapeutics Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USAZhicheng Wang - Department of Systems Pharmacology and Translational Therapeutics Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USA, Division of Pulmonary Allergy, and Critical Care Department of Medicine Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USAJacob S. Brenner - University of Pennsylvania
- Publication Details
- Advanced science, e17931
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:001721645300001
- Other Identifier
- 991022170442704721