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 7 publications

(6 citation statements)

References 47 publications

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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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“…FG Ti was a high-strength pure Ti with aligned bone-mimicking fibrous grains, obtained by extruding, rotary swaging and annealing CG Ti, which has been thoroughly characterized in our previous study [ 26 ]. Cationic lipid (RLS) was synthesized in our group as described previously [ 30 ]. Lipofectamine 2000 (Lipo 2000), a plasmid encoding enhanced green fluorescent proteins (pEGFP) and luciferase encoding plasmid (pGL3) were from Invitrogen (USA).…”

Section: Methodsmentioning

confidence: 99%

Fibrous topology promoted pBMP2-activated matrix on titanium implants boost osseointegration

He,

Wang,

Wang

et al. 2023

Regenerative Biomaterials

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Titanium (Ti) implants have been extensively used after surgical operations. Its surface bioactivity is of importance to facilitate integration with surrounding bone tissue, and ultimately ensure stability and long-term functionality of the implant. The plasmid DNA-activated matrix (DAM) coating on the surface could benefit osseointegration but is still trapped by poor transfection for further application, especially on the bone marrow mesenchymal stem cells (BMSCs) in vivo practical conditions. Herein, we constructed a DAM on the surface of fibrous-grained titanium (FG Ti) composed of phase-transition lysozyme (P) as adhesive, cationic arginine-rich lipid (RLS) as the transfection agent and plasmid DNA (pDNA) for bone morphology protein 2 (BMP2) expression. The cationic lipid RLS improved up to 30-fold higher transfection than that of commercial reagents (Lipofectamine 2000 and polyethyleneimine) on MSC. And importantly, Ti surface topology not only promotes the DAM to achieve high transfection efficiency (∼75.7% positive cells) on MSC due to the favorable combination but also reserves its contact induction effect for osteoblasts. Upon further exploration, the fibrous topology on FG Ti could boost pDNA uptake for gene transfection, and cell migration in MSC through cytoskeleton remodeling and induce contact guidance for enhanced osteointegration. At the same time, the cationic RLS together with adhesive P were both antibacterial, showing up to 90% inhibition rate against Escherichia coli and Staphylococcus aureus with reduced adherent microorganisms and disrupted bacteria. Finally, the FG Ti-P/pBMP2 implant achieved accelerated bone healing capacities through highly efficient gene delivery, aligned surface topological structure and increased antimicrobial properties in a rat femoral condylar defect model.

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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 7 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

Fibrous topology promoted pBMP2-activated matrix on titanium implants boost osseointegration

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