Fusogenic Coiled-Coil Peptides Enhance Lipid Nanoparticle-Mediated mRNA Delivery upon Intramyocardial Administration

Zeng, Ye; Estapé Senti, Mariona; Labonia, M. Clara I.; Papadopoulou, Panagiota; Brans, Maike A. D.; Dokter, Inge; Fens, Marcel H.; van Mil, Alain; Sluijter, Joost P. G.; Schiffelers, Raymond M.; Vader, Pieter; Kros, Alexander

doi:10.1021/acsnano.3c05341

Cited by 9 publications

(8 citation statements)

References 56 publications

(88 reference statements)

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“…M.VaderP.KrosA. Zeng, Y. Estapé Senti, M. Labonia, M. C. I. Papadopoulou, P. Brans, M. A. D. Dokter, I. Fens, M. H. van Mil, A. Sluijter, J. P. G. Schiffelers, R. M. Vader, P. Kros, A. 10.1021/acsnano.3c05341ACS Nano2023172346623477 …”

Section: Key Referencesmentioning

confidence: 99%

“…CPK4/CPE4-functionalized LNP formulations consistently showed enhanced mRNA transfection compared to that of their unfunctionalized counterparts in these cell lines. Altogether, functionalizing mRNA-LNPs with fusogenic coiled-coil peptides using a 1-step mixing approach significantly enhances mRNA transfection in HeLa and hard-to-transfect iPSC-CMs and Jurkat cells in vitro and improves local mRNA transfection upon intramyocardial administration in vivo …”

Section: Lipid-based Nanoparticles Functionalized With Fusogenic Pept...mentioning

confidence: 99%

“… 10.1021/acsnano.3c05341 37982378 ACS Nano 2023 17 23466 23477 . 4 Building upon previous reports, we expanded our scope to lipid nanoparticles (LNPs) as delivery vehicles. Here we decorated the LNPs and cells with fusogenic peptides to overcome the endocytic pathway, leading to increased protein expression levels compared to those of plain LNPs.…”

Section: Key Referencesmentioning

confidence: 99%

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Lipid-Based Nanoparticle Functionalization with Coiled-Coil Peptides for In Vitro and In Vivo Drug Delivery

Aschmann,

Knol,

Kros

2024

Acc. Chem. Res.

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Metrics & MoreArticle Recommendations CONSPECTUS: For the delivery of drugs, different nanosized drug carriers (e.g., liposomes, lipid nanoparticles, and micelles) have been developed in order to treat diseases that afflict society. Frequently, these vehicles are formed by the self-assembly of small molecules to encapsulate the therapeutic cargo of interest. Over decades, nanoparticles have been optimized to make them more efficient and specific to fulfill tailor-made tasks, such as specific cell targeting or enhanced cellular uptake. In recent years, lipid-based nanoparticles in particular have taken center stage; however, off-targeting side effects and poor endosomal escape remain major challenges since therapies require high efficacy and acceptable toxicity.To overcome these issues, many different approaches have been explored to make drug delivery more specific, resulting in reduced side effects, to achieve an optimal therapeutic effect and a lower required dose. The fate of nanoparticles is largely dependent on size, shape, and surface charge. A common approach to designing drug carriers with targeting capability is surface modification. Different approaches to functionalize nanoparticles have been investigated since the attachment of targeting moieties plays a significant role in whether they can later interact with surface-exposed receptors of cells. To this end, various strategies have been used involving different classes of biomolecules, such as small molecules, nucleic acids, antibodies, aptamers, and peptides. Peptides in particular are often used since there are many receptors overexpressed in different specific cell types. Furthermore, peptides can be produced and modified at a low cost, enabling high therapeutic screening. Cell-penetrating peptides (CPPs) and cell-targeting peptides (CTPs) are frequently used for this purpose. Less studied in this context are fusogenic coiled-coil peptides.Lipid-based nanoparticles functionalized with these peptides are able to avoid the endolysosomal pathway; instead such particles can be taken up by membrane fusion, resulting in increased delivery of payload. Furthermore, they can be used for targeting cells/organs but are not directed at surface-exposed receptors. Instead, they recognize complementary peptide sequences, facilitating their uptake into cells.In this Account, we will discuss peptides as moieties for enhanced cytosolic delivery, targeted uptake, and how they can be attached to lipid-based nanoparticles to alter their properties. We will discuss the properties imparted to the particles by peptides, surface modification approaches, and recent examples showing the power of peptides for in vitro and in vivo drug delivery. The main focus will be on the functionalization of lipid-based nanoparticles by fusogenic coiled-coil peptides, highlighting the relevance of this concept for the development of future therapeutics.

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Section: Key Referencesmentioning

confidence: 99%

Section: Lipid-based Nanoparticles Functionalized With Fusogenic Pept...mentioning

confidence: 99%

Section: Key Referencesmentioning

confidence: 99%

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Lipid-Based Nanoparticle Functionalization with Coiled-Coil Peptides for In Vitro and In Vivo Drug Delivery

Aschmann,

Knol,

Kros

2024

Acc. Chem. Res.

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“…This issue may be solved by engineering advanced transfection reagents for synthetic mRNAs. [20][21][22] This work not only realizes a useful tool for accurate cell separation but also highlights a feasible approach for differential protein regulation, which sheds light on the further development of advanced synthetic mRNA-based circuits.…”

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confidence: 99%

VPg-based bidirectional synthetic mRNA circuits enable orthogonal protein regulation for high-resolution cell separation

Liang,

Hu,

et al. 2024

Chem. Commun.

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“…For ingredient-optimization, a promising approach, termed the Selective ORgan Targeting (SORT) strategy, addresses precise organ (lung, spleen, and liver) delivery by enabling systematic engineering of LNPs through the incorporation of SORT lipid molecules . However, the addition of a fifth lipid component to LNPs introduces further formulation complexities. − Such intricacies may potentially impede regulatory approval processes and lead to manufacturing challenges. In addition, in vivo delivering mRNA to specific cell types for precise protein expression remains a technical challenge, due to the complex structure, multifunctional nature, and diverse cell populations within organs. , For instance, the liver-targeting strategy highlights the need for highly specialized delivery systems to target mRNA therapeutics to distinct cell types, such as hepatocytes for metabolic correction, liver sinusoidal endothelial cells (LSECs) for homeostasis regulation, or Kupffer cells for immune modulation. − Developing such targeted delivery systems is crucial for maximizing the efficacy of mRNA-mediated therapies.…”

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confidence: 99%

Helper Lipid-Enhanced mRNA Delivery for Treating Metabolic Dysfunction-Associated Fatty Liver Disease

Guo,

Zeng,

Shen

et al. 2024

Nano Lett.

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Lipid nanoparticles (LNPs) represent the forefront of mRNA delivery platforms, yet achieving precise delivery to specific cells remains a challenge. The current targeting strategies complicate the formulation and impede the regulatory approval process. Here, through a straightforward regulation of helper lipids within LNPs, we introduce an engineered LNP designed for targeted delivery of mRNA into hepatocytes for metabolic dysfunction-associated fatty liver disease (MAFLD) treatment. The optimized LNP, supplied with POPC as the helper lipid, exhibits a 2.49-fold increase in mRNA transfection efficiency in hepatocytes compared to that of FDA-approved LNPs. CTP:phosphocholine cytidylyltransferase α mRNA is selected for delivery to hepatocytes through the optimized LNP system for self-calibration of phosphatidylcholine levels to prevent lipid droplet expansion in MAFLD. This strategy effectively regulates lipid homeostasis, while demonstrating proven biosafety. Our results present a mRNA therapy for MAFLD and open a new avenue for discovering potent lipids enabling mRNA delivery to specific cells.

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Fusogenic Coiled-Coil Peptides Enhance Lipid Nanoparticle-Mediated mRNA Delivery upon Intramyocardial Administration

Cited by 9 publications

References 56 publications

Lipid-Based Nanoparticle Functionalization with Coiled-Coil Peptides for In Vitro and In Vivo Drug Delivery

Lipid-Based Nanoparticle Functionalization with Coiled-Coil Peptides for In Vitro and In Vivo Drug Delivery

VPg-based bidirectional synthetic mRNA circuits enable orthogonal protein regulation for high-resolution cell separation

Helper Lipid-Enhanced mRNA Delivery for Treating Metabolic Dysfunction-Associated Fatty Liver Disease

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