A cationic lipid with advanced membrane fusion performance for pDNA and mRNA delivery

Wei, Yu Quan; He, Ting; Bi, Qunjie; Yang, Huan; Hu, Xueyi; Jin, Rongrong; Liang, Hong; Zhu, Yongqu; Tong, Rongsheng; Nie, Yu

doi:10.1039/d2tb02783f

Cited by 5 publications

(4 citation statements)

References 47 publications

(59 reference statements)

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“…Also, other favorable mechanisms such as membrane fusion events might be involved in effective intracellular uptake, as was demonstrated for lipoplexes in other work. [ 2a,32 ] This needs to be clarified in subsequent investigations.…”

Section: Resultsmentioning

confidence: 99%

“…Additional shielding and targeting measures could be further improvements. Further chemical evolution of our sequence‐defined libraries in this interesting chemical lipoamino space, and a better rational understanding of the ultrastructure (by Cryo‐TEM, SAXS, or other methods) and molecular cell entry mechanisms [ 32,42 ] will contribute to finding the sweet spot between lipoplexes and polyplexes.…”

Section: Discussionmentioning

confidence: 99%

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Molecular Chameleon Carriers for Nucleic Acid Delivery: The Sweet Spot between Lipoplexes and Polyplexes

et al. 2023

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Taking advantage of effective intracellular delivery mechanisms of both cationizable lipids and polymers, highly potent double pH-responsive nucleic acid carriers are generated by combining at least two lipo amino fatty acids (LAFs) as hydrophobic cationizable motifs with hydrophilic cationizable aminoethylene units into novel sequence-defined molecules. The pH-dependent tunable polarity of the LAF is successfully implemented by inserting a central tertiary amine, which disrupts the hydrophobic character once protonated, resulting in pH-dependent structural and physical changes. This "molecular chameleon character" turns out to be advantageous for dynamic nucleic acid delivery via lipopolyplexes. By screening different topologies (blocks, bundles, T-shapes, U-shapes), LAF types, and LAF/aminoethylene ratios, highly potent pDNA, mRNA, and siRNA carriers are identified, which are up to several 100-fold more efficient than previous carrier generations and characterized by very fast transfection kinetics. mRNA lipopolyplexes maintain high transfection activity in cell culture even in the presence of ≥90% serum at an ultra-low mRNA dose of 3 picogram (≈2 nanoparticles/cell), and thus are comparable in potency to viral nanoparticles. Importantly, they show great in vivo performance with high expression levels especially in spleen, tumor, lungs, and liver upon intravenous administration of 1-3 μg luciferase-encoding mRNA in mice.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Molecular Chameleon Carriers for Nucleic Acid Delivery: The Sweet Spot between Lipoplexes and Polyplexes

et al. 2023

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“…To determine whether PEVs and CRT hi M were hybrid in the surface of the PLGA core, a fluorescence resonance energy transfer (FRET) assay was used to yield a quantitative evaluation. , PEVs were initially labeled with Cy3/Cy3.5 dyes (1:3, w/w) to generate FRET at an excitation wavelength of 545 nm. Fluorescence emission increased at 563.0 and 605.0 nm as a high rate of CRT hi M was added, indicating reduction of FRET and successful membrane fusion (Figure f).…”

Section: Resultsmentioning

confidence: 99%

Aged-Signal-Eliciting Nanoparticles Stimulated Macrophage-Mediated Programmed Removal of Inflammatory Neutrophils

et al. 2023

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Excessive infiltration of activated neutrophils is regarded as a predominant cause of tissue injury in neutrophilic inflammation. Although programmed cell death like apoptosis maintains the homeostasis of activated neutrophils, this process is disrupted by an abnormal inflammatory response. Unlike endogenous calreticulin exposed during apoptosis, exogenous calreticulin acts as an “aged” signal and initiates premature macrophage-mediated programmed cell removal (PrCR), which is independent of apoptosis. Here, we report a nano-mediated strategy to stimulate the precise clearance of activated neutrophils initiated with artificial aged signal and alleviated inflammation. Polymeric nanoparticles PC@PLGA were fabricated by cloaking poly(lactic-co-glycolic acid) (PLGA) with a hybrid membrane derived from platelet-derived extracellular vesicles (PEVs, denoted by P) and the calreticulin-expressed membrane obtained from doxorubicin-treated cells (denoted by C). P-selectin in PEVs favors PC@PLGA to anchor activated neutrophils, while calreticulin mimics exogenous “aged” signal secreted by macrophages to trigger PrCR. We showed that PC@PLGA specifically targeted activated neutrophils and misled macrophages to recognize them as “aged” neutrophils and then initiated premature PrCR and prevented proinflammatory response and tissue damage in a mouse model of acute lung injury and severe acute pancreatitis. The collective findings indicate the efficiency of specific elimination of activated neutrophils with exogenous aged signal in improving inflammation therapy.

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“…[234] In another study, the introduction of unsaturated bonds into hydrophobic chains of cationic lipids could significantly promote internalization efficiency of mRNA lipoplexes by enhancing membrane fusion performance. [235] It was also reported that fluorinated LNPs and polymeric nanocarriers could promote cellular uptake and mRNA delivery efficiency due to the hydrophobic and lipophobic dual characteristics and high phase-separation tendency of fluorinated segments. [236,237] Physiochemical properties of nanocarriers, such as size, charge, and stereochemistry also have impacts on cellular internalization.…”

Section: Engineering the Nanocarriersmentioning

confidence: 99%

Cellular Trafficking of Nanotechnology‐Mediated mRNA Delivery

Huang,

Deng,

Wang

et al. 2023

Advanced Materials

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Messenger RNA (mRNA)‐based therapy has emerged as a powerful, safe, and rapidly scalable therapeutic approach that involves technologies for both mRNA itself and the delivery vehicle. Although there are some unique challenges for different applications of mRNA therapy, a common challenge for all mRNA therapeutics is the transport of mRNA into the target cell cytoplasm for sufficient protein expression. This review is focused on the behaviors at the cellular level of nanotechnology‐mediated mRNA delivery systems, which have not been comprehensively reviewed yet. First, the four main therapeutic applications of mRNA are introduced, including immunotherapy, protein replacement therapy, genome editing, and cellular reprogramming. Second, common types of mRNA cargos and mRNA delivery systems are summarized. Third, strategies to enhance mRNA delivery efficiency during the cellular trafficking process are highlighted, including accumulation to the cell, internalization into the cell, endosomal escape, release of mRNA from the nanocarrier, and translation of mRNA into protein. Finally, the challenges and opportunities for the development of nanotechnology‐mediated mRNA delivery systems are presented. This review can provide new insights into the future fabrication of mRNA nanocarriers with desirable cellular trafficking performance.

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A cationic lipid with advanced membrane fusion performance for pDNA and mRNA delivery

Abstract: The success of mRNA vaccines for COVID-19 prevention raised global awareness of the importance of nucleic acid drugs. The approved systems for nucleic acid delivery were mainly formulations of different...

Cited by 5 publications

References 47 publications

Molecular Chameleon Carriers for Nucleic Acid Delivery: The Sweet Spot between Lipoplexes and Polyplexes

Molecular Chameleon Carriers for Nucleic Acid Delivery: The Sweet Spot between Lipoplexes and Polyplexes

Aged-Signal-Eliciting Nanoparticles Stimulated Macrophage-Mediated Programmed Removal of Inflammatory Neutrophils

Cellular Trafficking of Nanotechnology‐Mediated mRNA Delivery

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