Journal article
Limiting endosomal damage sensing reduces inflammation triggered by lipid nanoparticle endosomal escape
Nature nanotechnology, v 20(9), pp 1285-1297
11 Aug 2025
PMID: 40789922
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Lipid nanoparticles (LNPs) have emerged as the dominant platform for RNA delivery, but they induce severe inflammation. Here we show that LNPs’ hallmark feature, endosomal escape, which is necessary for RNA expression, also triggers inflammation by causing endosomal membrane damage. Large, irreparable, endosomal holes are recognized by cytosolic proteins called galectins, which regulate downstream inflammation. We find that inhibition of galectins abrogates LNP-associated inflammation, both in vitro and in vivo. Moreover, we show that a unique class of ionizable lipids can create smaller endosomal holes, reparable by the endosomal sorting complex required for transport (ESCRT) pathway. Such lipids can produce high expression from cargo messenger RNA with minimal inflammation. Finally, we show that both galectin inhibition or ESCRT-recruiting ionizable lipids allow for treatment of highly inflammatory disease models by therapeutic mRNAs. These strategies should lead to safer non-inflammatory LNPs that can be generally used to treat inflammatory diseases.
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Details
- Title
- Limiting endosomal damage sensing reduces inflammation triggered by lipid nanoparticle endosomal escape
- Creators
- Serena Omo-Lamai - University of PennsylvaniaYufei Wang - University of PennsylvaniaManthan N. Patel - University of PennsylvaniaAleksa Milosavljevic - University of PennsylvaniaDaniel Zuschlag - University of PennsylvaniaSubhajit Poddar - University of PennsylvaniaJichuan Wu - University of PennsylvaniaLiuqian Wang - University of PennsylvaniaFengyi Dong - University of PennsylvaniaCarolann Espy - University of PennsylvaniaAparajeeta Majumder - University of PennsylvaniaEno-Obong EssienMengwen Shen - Yueyang HospitalBreana Channer - Drexel UniversityTyler E. Papp - University of PennsylvaniaMichael Tobin - University of PennsylvaniaRhea Maheshwari - Case Western Reserve UniversitySumin JeongSofia PatelAnit Shah - University of PennsylvaniaShruthi Murali - University of PennsylvaniaLiam S. Chase - University of PennsylvaniaMarco E. Zamora - University of PennsylvaniaMariah L. Arral - Carnegie Mellon UniversityOscar A. Marcos-Contreras - University of PennsylvaniaJacob W. Myerson - University of PennsylvaniaChristopher A. Hunter - University of PennsylvaniaDennis Discher - University of PennsylvaniaPeter J. Gaskill - Drexel UniversityAndrew Tsourkas - University of PennsylvaniaVladimir R. Muzykantov - University of PennsylvaniaIgor Brodsky - University of PennsylvaniaSunny Shin - University of PennsylvaniaKathryn A. Whitehead - Carnegie Mellon UniversityHamideh Parhiz - University of PennsylvaniaJeremy Katzen - University of PennsylvaniaJonathan J. Miner - University of PennsylvaniaDirk Trauner - University of PennsylvaniaJacob S. Brenner - University of Pennsylvania
- Publication Details
- Nature nanotechnology, v 20(9), pp 1285-1297
- Publisher
- NATURE
- Number of pages
- 21
- Grant note
- U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI): 23PRE1014444, 24PRE1195406 American Heart Association: 1F31AG077874-01 NIH F31 fellowship: F31HL154662, NIH R01 NS 131279, NIH R61DA058501, R01DA057337 Ruth L. Kirschstein National Research Service Award (NRSA): 5K08HL150226, NIH R01 HL157189 Pulmonary Fibrosis Foundation Tully Family Familial Pulmonary Fibrosis Research Award: R01HL153510, R01 HL60694, R01 HL164594, R41 NS130812 NIH
Research reported in this publication was supported by the American Heart Association under grant 23PRE1014444 (to S.O.-L.) and grant 24PRE1195406 (to M.N.P.), NIH F31 fellowship (award number 1F31AG077874-01) (to M.L.A.), Ruth L. Kirschstein National Research Service Award (NRSA) F31HL154662 (to M.E.Z.), grant NIH R01 NS 131279 (to O.A.M.-C.), grant NIH R61DA058501, R01DA057337 (to P.J.G.), Pulmonary Fibrosis Foundation Tully Family Familial Pulmonary Fibrosis Research Award, grant 5K08HL150226 (to J.K.) and grant NIH R01 HL157189 (to V.R.M., J.W.M. and J.S.B.), and grants NIH R01HL153510, R01 HL60694, R01 HL164594 and R41 NS130812 (to J.S.B.).
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology; School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:001546944200001
- Scopus ID
- 2-s2.0-105012882876
- Other Identifier
- 991022080095304721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Materials Science, Multidisciplinary
- Nanoscience & Nanotechnology