Preprint
Lipid Nanoparticle-Associated Inflammation is Triggered by Sensing of Endosomal Damage: Engineering Endosomal Escape Without Side Effects
bioRxiv : the preprint server for biology
18 Apr 2024
PMID: 38659905
Abstract
Lipid nanoparticles (LNPs) have emerged as the dominant platform for RNA delivery, based on their success in the COVID-19 vaccines and late-stage clinical studies in other indications. However, we and others have shown that LNPs induce severe inflammation, and massively aggravate pre-existing inflammation. Here, using structure-function screening of lipids and analyses of signaling pathways, we elucidate the mechanisms of LNP-associated inflammation and demonstrate solutions. We show that LNPs' hallmark feature, endosomal escape, which is necessary for RNA expression, also directly triggers inflammation by causing endosomal membrane damage. Large, irreparable, endosomal holes are recognized by cytosolic proteins called galectins, which bind to sugars on the inner endosomal membrane and then regulate downstream inflammation. We find that inhibition of galectins abrogates LNP-associated inflammation, both
and
. We show that rapidly biodegradable ionizable lipids can preferentially create endosomal holes that are smaller in size and reparable by the endosomal sorting complex required for transport (ESCRT) pathway. Ionizable lipids producing such ESCRT-recruiting endosomal holes can produce high expression from cargo mRNA with minimal inflammation. Finally, we show that both routes to non-inflammatory LNPs, either galectin inhibition or ESCRT-recruiting ionizable lipids, are compatible with therapeutic mRNAs that ameliorate inflammation in disease models. LNPs without galectin inhibition or biodegradable ionizable lipids lead to severe exacerbation of inflammation in these models. In summary, endosomal escape induces endosomal membrane damage that can lead to inflammation. However, the inflammation can be controlled by inhibiting galectins (large hole detectors) or by using biodegradable lipids, which create smaller holes that are reparable by the ESCRT pathway. These strategies should lead to generally safer LNPs that can be used to treat inflammatory diseases.
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Details
- Title
- Lipid Nanoparticle-Associated Inflammation is Triggered by Sensing of Endosomal Damage: Engineering Endosomal Escape Without Side Effects
- Creators
- Serena Omo-LamaiYufei Wang - California University of PennsylvaniaManthan N PatelEno-Obong EssienMengwen Shen - Yueyang HospitalAparajeeta MajumdarCarolann Espy - California University of PennsylvaniaJichuan Wu - California University of PennsylvaniaBreana Channer - Drexel UniversityMichael Tobin - California University of PennsylvaniaShruthi Murali - California University of PennsylvaniaTyler E Papp - California University of PennsylvaniaRhea Maheshwari - Case Western Reserve UniversityLiuqian Wang - California University of PennsylvaniaLiam S ChaseMarco E Zamora - Drexel UniversityMariah L Arral - Carnegie Mellon UniversityOscar A Marcos-ContrerasJacob W Myerson - California University of PennsylvaniaChristopher A Hunter - California University of PennsylvaniaAndrew Tsourkas - California University of PennsylvaniaVladimir Muzykantov - California University of PennsylvaniaIgor Brodsky - California University of PennsylvaniaSunny Shin - California University of PennsylvaniaKathryn A Whitehead - Carnegie Mellon UniversityPeter Gaskill - Drexel UniversityDennis Discher - California University of PennsylvaniaHamideh Parhiz - California University of PennsylvaniaJacob S Brenner - California University of Pennsylvania
- Publication Details
- bioRxiv : the preprint server for biology
- Publisher
- American Physical Society (APS); United States
- Resource Type
- Preprint
- Language
- English
- Academic Unit
- Pharmacology and Physiology; School of Biomedical Engineering and Science
- Other Identifier
- 991021869043204721