Engineered Lipid Nanoparticles for the Treatment of Pulmonary Fibrosis by Regulating Epithelial‐Mesenchymal Transition in the Lungs

Jin, Hee Kyung; Jeong, Michaela; Lee, Gyeongseok; Kim, Minjeong; Yoo, Youngjo; Kim, Hyun Jin; Cho, Jaeho; Lee, Yun‐Sil; Lee, Hyukjin

doi:10.1002/adfm.202209432

Cited by 11 publications

(5 citation statements)

References 34 publications

(40 reference statements)

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“…We first probed the inflammation induced in various systems by mRNA-LNPs fabricated with one of the best-studied ionizable lipids, cKK-E12, which is among the top-reported ionizable lipids for driving strong RNA expression 25 (Supplementary Table 1). Into healthy, wildtype mice, we intratracheally instilled LNPs containing an mRNA dose ranging from 2.5µg -10µg per mouse, which are therapeutically relevant doses for intratracheal LNP treatment 26,27 . Animals were sacrificed 24h after LNP treatment.…”

Section: Lnps Induce Potent Inflammation In Vitro and In Vivo Across ...mentioning

confidence: 99%

Lipid Nanoparticle-Associated Inflammation is Triggered by Sensing of Endosomal Damage: Engineering Endosomal Escape Without Side Effects

Omo-Lamai,

Wang,

Patel

et al. 2024

Preprint

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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 in vitro and in vivo. 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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Section: Lnps Induce Potent Inflammation In Vitro and In Vivo Across ...mentioning

confidence: 99%

Lipid Nanoparticle-Associated Inflammation is Triggered by Sensing of Endosomal Damage: Engineering Endosomal Escape Without Side Effects

Omo-Lamai,

Wang,

Patel

et al. 2024

Preprint

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“…Jin et al also designed a novel type of LNP for the pulmonary delivery of siRNA. [160] The LNP formation with a novel ionizable lipid 246C10, cholesterol, DSPC, and C16-PEG-mannose exhibited efficient delivery of siRNA and down-regulating the epithelial-mesenchymal transition (EMT)-related protein expression. Even though there are various structures of ionizable lipids in different LNP systems, they all share the same endosomal escape mechanism, suggesting an attractive route for mRNA and other genetic drug pulmonary delivery.…”

Section: Regulate Intracellular Releasementioning

confidence: 99%

Recent Progress in Nucleic Acid Pulmonary Delivery toward Overcoming Physiological Barriers and Improving Transfection Efficiency

Wang,

Bu,

Dai

et al. 2024

Advanced Science

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Pulmonary delivery of therapeutic agents has been considered the desirable administration route for local lung disease treatment. As the latest generation of therapeutic agents, nucleic acid has been gradually developed as gene therapy for local diseases such as asthma, chronic obstructive pulmonary diseases, and lung fibrosis. The features of nucleic acid, specific physiological structure, and pathophysiological barriers of the respiratory tract have strongly affected the delivery efficiency and pulmonary bioavailability of nucleic acid, directly related to the treatment outcomes. The development of pharmaceutics and material science provides the potential for highly effective pulmonary medicine delivery. In this review, the key factors and barriers are first introduced that affect the pulmonary delivery and bioavailability of nucleic acids. The advanced inhaled materials for nucleic acid delivery are further summarized. The recent progress of platform designs for improving the pulmonary delivery efficiency of nucleic acids and their therapeutic outcomes have been systematically analyzed, with the application and the perspectives of advanced vectors for pulmonary gene delivery.

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“…[140] In another study, Jin et al utilized intratracheal injection to deliver mannose-modified LNPs for the treatment of pulmonary fibrosis. [141] In addition, Yu et al developed nerve growth factor mutant (NGF R100W ) mRNA-LNPs and injected them locally at the hind paw to treat chemotherapy-induced peripheral neuropathy. [142] Riley et al utilized LNPs to achieve in utero mRNA delivery by directly injecting them through the vitelline vein.…”

Section: Choice Of Administration Routesmentioning

confidence: 99%

Lipid Nanoparticle (LNP) Enables mRNA Delivery for Cancer Therapy

et al. 2023

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Messenger RNA (mRNA) has received great attention in the prevention and treatment of various diseases due to the success of COVID‐19 mRNA vaccines (Comirnaty and Spikevax). To meet the therapeutic purpose, it is required that mRNA must enter the target cells and express sufficient proteins. Therefore, the development of effective delivery systems is necessary and crucial. Lipid nanoparticle (LNP) represents a remarkable vehicle that has indeed accelerated mRNA applications in humans, as several mRNA‐based therapies have already been approved or are in clinical trials. In this review, we focus on mRNA‐LNP mediated anticancer therapy. We summarize the main development strategies of mRNA‐LNP formulations, discuss representative therapeutic approaches in cancer, and point out current challenges and possible future directions of this research field. We hope these delivered messages could help further improve the application of mRNA‐LNP technology in cancer therapy.This article is protected by copyright. All rights reserved

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Engineered Lipid Nanoparticles for the Treatment of Pulmonary Fibrosis by Regulating Epithelial‐Mesenchymal Transition in the Lungs

Cited by 11 publications

References 34 publications

Lipid Nanoparticle-Associated Inflammation is Triggered by Sensing of Endosomal Damage: Engineering Endosomal Escape Without Side Effects

Lipid Nanoparticle-Associated Inflammation is Triggered by Sensing of Endosomal Damage: Engineering Endosomal Escape Without Side Effects

Recent Progress in Nucleic Acid Pulmonary Delivery toward Overcoming Physiological Barriers and Improving Transfection Efficiency

Lipid Nanoparticle (LNP) Enables mRNA Delivery for Cancer Therapy

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