Optimization of lipid nanoparticles for the delivery of nebulized therapeutic mRNA to the lungs

Lokugamage, Melissa P.; Vanover, Daryll; Beyersdorf, Jared; Hatit, Marine Z. C.; Rotolo, Laura; Echeverri, Elisa Schrader; Peck, Hannah E.; Ni, Huanzhen; Yoon, Jeong‐Kee; Kim, Yong Tae; Santangelo, Philip J.; Dahlman, James E.

doi:10.1038/s41551-021-00786-x

Cited by 270 publications

(180 citation statements)

References 66 publications

Supporting

Mentioning

177

Contrasting

Order By: Relevance

“…We have demonstrated that PACE polymer formulations can be optimized and applied for local mRNA delivery to the lung. We employed a screening method for optimizing polyplexes, a strategy which has previously been employed for lipopolyplex (25) and LNP (35)(36)(37) optimization. LNP optimization often requires screening varying ratios of four component variables, generating large and unwieldy chemical spaces.…”

Section: Discussionmentioning

confidence: 99%

Inhalable polymer nanoparticles for versatile mRNA delivery and mucosal vaccination

Suberi

Grun

Mao

et al. 2022

Preprint

View full text Add to dashboard Cite

An inhalable platform for mRNA therapeutics would enable minimally invasive and lung targeted delivery for a host of pulmonary diseases. Development of lung targeted mRNA therapeutics has been limited by poor transfection efficiency and risk of vehicle-induced pathology. Here we report an inhalable polymer-based vehicle for delivery of therapeutic mRNAs to the lung. We optimized biodegradable poly(amine-co-ester) polyplexes for mRNA delivery using end group modifications and polyethylene glycol. Our polyplexes achieved high transfection of mRNA throughout the lung, particularly in epithelial and antigen-presenting cells. We applied this technology to develop a mucosal vaccine for SARS-CoV-2. Intranasal vaccination with spike protein mRNA polyplexes induced potent cellular and humoral adaptive immunity and protected K18-hACE2 mice from lethal viral challenge.

show abstract

Section: Discussionmentioning

confidence: 99%

Inhalable polymer nanoparticles for versatile mRNA delivery and mucosal vaccination

Suberi

Grun

Mao

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Although most preclinical studies have evaluated how the structure of the cationic or ionizable lipid influences delivery, the other three components can also affect delivery 131 , 132 . For example, by changing the cholesterol, PEG-lipid or ‘helper’ lipid, an LNP that delivered siRNA to pulmonary and cardiovascular endothelial cells in mice 133 and non-human primates 134 was retargeted to deliver siRNA 135 , sgRNA 136 or mRNA 99 to bone marrow, hepatic and splenic endothelial cells after intravenous administration as well as lung epithelial cells after nebulization 137 . In additional examples, changing the PEG-lipid structure or its molar percentage altered LNP pharmacokinetics and liver siRNA delivery 138 in mice and affected delivery within the eye 139 .…”

Section: Synthetic Vehicles For Rna Deliverymentioning

confidence: 99%

Drug delivery systems for RNA therapeutics

2022

Self Cite

View full text Add to dashboard Cite

RNA-based gene therapy requires therapeutic RNA to function inside target cells without eliciting unwanted immune responses. RNA can be ferried into cells using non-viral drug delivery systems, which circumvent the limitations of viral delivery vectors. Here, we review the growing number of RNA therapeutic classes, their molecular mechanisms of action, and the design considerations for their respective delivery platforms. We describe polymer-based, lipid-based, and conjugate-based drug delivery systems, differentiating between those that passively and those that actively target specific cell types. Finally, we describe the path from preclinical drug delivery research to clinical approval, highlighting opportunities to improve the efficiency with which new drug delivery systems are discovered.

show abstract

“…Intramuscular, intradermal, and intratracheal administration of LNP-encapsulated mRNA have been found to produce higher and more prolonged protein levels at the site of inoculation than those produced by systemic delivery [195]. However, LNP needs to be specifically designed and optimized for the efficient pulmonary delivery of IVT-mRNA [199]. In one study, cationic LNPs and mannose-conjugated LNP (Man-LNP) were separately applied to encapsulate IVT-mRNA encoding the HA gene of the H1N1 influenza A virus.…”

Section: Lipidsmentioning

confidence: 99%

“…The chloride response in two consecutive doses of CFTR-mRNA/LNP-treated mice recovered up to 55% of the levels observed in wild-type mice and lasted up to 2 weeks posttransfection [200]. Motivated by the huge unmet needs for lung IVT-mRNA delivery vehicles, as well as by the lack of established LNP design principles, Lokugamage et al recently reported an in vivo cluster-based iterative screening approach to identify LNP chemical traits that promote IVT-mRNA lung delivery [199]. They discovered that a low PEG molar ratio increased the performance of LNPs with neutral helper lipids, whereas a high PEG molar ratio improved the performance of cationic helper lipids, uncovering and optimizing LNPs for low-dose IVT-mRNA delivery.…”

Section: Lipidsmentioning

confidence: 99%

Nanotechnologies in Delivery of DNA and mRNA Vaccines to the Nasal and Pulmonary Mucosa

Tang

Cai

et al. 2022

Nanomaterials

View full text Add to dashboard Cite

Recent advancements in the field of in vitro transcribed mRNA (IVT-mRNA) vaccination have attracted considerable attention to such vaccination as a cutting-edge technique against infectious diseases including COVID-19 caused by SARS-CoV-2. While numerous pathogens infect the host through the respiratory mucosa, conventional parenterally administered vaccines are unable to induce protective immunity at mucosal surfaces. Mucosal immunization enables the induction of both mucosal and systemic immunity, efficiently removing pathogens from the mucosa before an infection occurs. Although respiratory mucosal vaccination is highly appealing, successful nasal or pulmonary delivery of nucleic acid-based vaccines is challenging because of several physical and biological barriers at the airway mucosal site, such as a variety of protective enzymes and mucociliary clearance, which remove exogenously inhaled substances. Hence, advanced nanotechnologies enabling delivery of DNA and IVT-mRNA to the nasal and pulmonary mucosa are urgently needed. Ideal nanocarriers for nucleic acid vaccines should be able to efficiently load and protect genetic payloads, overcome physical and biological barriers at the airway mucosal site, facilitate transfection in targeted epithelial or antigen-presenting cells, and incorporate adjuvants. In this review, we discuss recent developments in nucleic acid delivery systems that target airway mucosa for vaccination purposes.

show abstract

Optimization of lipid nanoparticles for the delivery of nebulized therapeutic mRNA to the lungs

Cited by 270 publications

References 66 publications

Inhalable polymer nanoparticles for versatile mRNA delivery and mucosal vaccination

Inhalable polymer nanoparticles for versatile mRNA delivery and mucosal vaccination

Drug delivery systems for RNA therapeutics

Nanotechnologies in Delivery of DNA and mRNA Vaccines to the Nasal and Pulmonary Mucosa

Contact Info

Product

Resources

About