Nucleic Acid Delivery by Solid Lipid Nanoparticles Containing Switchable Lipids: Plasmid DNA vs. Messenger RNA

Gómez-Aguado, Itziar; Rodríguez-Castejón, Julen; Vicente-Pascual, Mónica; Rodríguez-Gascón, Alicia; Pozo-Rodríguez, Ana del; Aspiazu, María Ángeles Solinís

doi:10.3390/molecules25245995

Cited by 37 publications

(27 citation statements)

References 42 publications

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“…In the last decades, considerable advances have been made in the conception of nucleic acid-based delivery systems to overcome the major drawbacks of payload delivery to eukaryotic cells, namely, cellular uptake/internalization, endosomal escape, targeting a specific subcellular compartment, and ultimately, the induction of therapeutic action [19,[21][22][23][24]. In line with this aim, micelles, polymers, lipid-and peptide-based nanoparticles are among the most studied systems for gene release [25][26][27][28]. In particular, cell-penetrating peptides (CPP) offer exceptional properties to be explored as gene delivery vehicles for successful gene therapy [28][29][30][31][32].…”

Section: Introductionmentioning

confidence: 99%

Development of Peptide-Based Nanoparticles for Mitochondrial Plasmid DNA Delivery

et al. 2021

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A mitochondrion is a cellular organelle able to produce cellular energy in the form of adenosine triphosphate (ATP). As in the nucleus, mitochondria contain their own genome: the mitochondrial DNA (mtDNA). This genome is particularly susceptible to mutations that are at the basis of a multitude of disorders, especially those affecting the heart, the central nervous system and muscles. Conventional clinical practice applied to mitochondrial diseases is very limited and ineffective; a clear need for innovative therapies is demonstrated. Gene therapy seems to be a promising approach. The use of mitochondrial DNA as a therapeutic, optimized by peptide-based complexes with mitochondrial targeting, can be seen as a powerful tool in the reestablishment of normal mitochondrial function. In line with this requirement, in this work and for the first time, a mitochondrial-targeting sequence (MTS) has been incorporated into previously researched peptides, to confer on them a targeting ability. These peptides were then considered to complex a plasmid DNA (pDNA) which contains the mitochondrial gene ND1 (mitochondrially encoded NADH dehydrogenase 1 protein), aiming at the formation of peptide-based nanoparticles. Currently, the ND1 plasmid is one of the most advanced bioengineered vectors for conducting research on mitochondrial gene expression. The formed complexes were characterized in terms of pDNA complexation capacity, morphology, size, surface charge and cytotoxic profile. These data revealed that the developed carriers possess suitable properties for pDNA delivery. Furthermore, in vitro studies illustrated the mitochondrial targeting ability of the novel peptide/pDNA complexes. A comparison between the different complexes revealed the most promising ones that complex pDNA and target mitochondria. This may contribute to the optimization of peptide-based non-viral systems to target mitochondria, instigating progress in mitochondrial gene therapy.

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Section: Introductionmentioning

confidence: 99%

Development of Peptide-Based Nanoparticles for Mitochondrial Plasmid DNA Delivery

et al. 2021

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“…Other advantages of using pDNA versus mRNA include the possibility to obtain abundant purified pDNA easily and economically, and the opportunity to perform repeated administrations without triggering an immune response [ 30 ]. Nevertheless, pDNA transfection is more difficult than that of mRNA, mainly due to the nuclear entry barrier [ 25 ]. In earlier studies, our research group has demonstrated the potential of SLN-based vectors-mediated pDNA delivery encoding α-Gal A to produce the enzyme in a liver-derived cell line (Hep G2) [ 26 ] and in a cell model of FD [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

“…The increase of α-Gal A activity observed after IV administration to mice of either the naked pDNA or the SLN-based vector, demonstrate their ability to circulate in the bloodstream and reach the tissues. Contrary to the naked pDNA, the SLN-based vector provides a higher stability to the pDNA and facilitates its internalization by the cells, which may explain the higher efficacy [ 21 , 25 , 26 , 27 , 28 ]. After the administration of the SLN-based vector once a week for three weeks, heart and kidney (the most important target organs) were the tissues where the greatest difference in α-Gal A activity between the naked pDNA and the SLN-based vector was detected.…”

Section: Discussionmentioning

confidence: 99%

“…Electrostatic interactions between negative and positive charges of the components led to the formation of the final DX-P-pDNA-SLN vector, in which DX-P-pDNA complexes were adsorbed on the surface of the SLNs. The final composition of the SLN-based vector is based on previous studies [ 21 , 25 , 26 , 27 , 28 ], in which different vectors carrying pDNA encoding GFP or α-Gal A were characterized in terms of encapsulation efficacy, capacity to bind, protect and release the gene cargo, Transmission Electron Microscopy (TEM), stability, in vitro transfection efficacy, cellular uptake and cell viability.…”

Section: Methodsmentioning

confidence: 99%

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α-Galactosidase A Augmentation by Non-Viral Gene Therapy: Evaluation in Fabry Disease Mice

et al. 2021

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Fabry disease (FD) is a monogenic X-linked lysosomal storage disorder caused by a deficiency in the lysosomal enzyme α-Galactosidase A (α-Gal A). It is a good candidate to be treated with gene therapy, in which moderately low levels of enzyme activity should be sufficient for clinical efficacy. In the present work we have evaluated the efficacy of a non-viral vector based on solid lipid nanoparticles (SLN) to increase α-Gal A activity in an FD mouse model after intravenous administration. The SLN-based vector incremented α-Gal A activity to about 10%, 15%, 20% and 14% of the levels of the wild-type in liver, spleen, heart and kidney, respectively. In addition, the SLN-based vector significantly increased α-Gal A activity with respect to the naked pDNA used as a control in plasma, heart and kidney. The administration of a dose per week for three weeks was more effective than a single-dose administration. Administration of the SLN-based vector did not increase liver transaminases, indicative of a lack of toxicity. Additional studies are necessary to optimize the efficacy of the system; however, these results reinforce the potential of lipid-based nanocarriers to treat FD by gene therapy.

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“…SLN EE were elaborated as previously reported [33], with the solid lipid Precirol ® ATO 5 and the cationic lipid DOTAP, stabilized by the surfactant Tween 80. Briefly, SLN EE were obtained by the sonication (Branson Sonifier 250, Danbury) of the organic phase (Precirol ® ATO 5 dissolved in dichloromethane 5% w/v) in the aqueous phase, containing the cationic lipid DOTAP (0.4% w/v) and Tween 80 (0.1% w/v).…”

Section: Formulation Of Slns and Vectorsmentioning

confidence: 99%

mRNA-Based Nanomedicinal Products to Address Corneal Inflammation by Interleukin-10 Supplementation

et al. 2021

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The anti-inflammatory cytokine Interleukin-10 (IL-10) is considered an efficient treatment for corneal inflammation, in spite of its short half-life and poor eye bioavailability. In the present work, mRNA-based nanomedicinal products based on solid lipid nanoparticles (SLNs) were developed in order to produce IL-10 to treat corneal inflammation. mRNA encoding green fluorescent protein (GFP) or human IL-10 was complexed with different SLNs and ligands. After, physicochemical characterization, transfection efficacy, intracellular disposition, cellular uptake and IL-10 expression of the nanosystems were evaluated in vitro in human corneal epithelial (HCE-2) cells. Energy-dependent mechanisms favoured HCE-2 transfection, whereas protein production was influenced by energy-independent uptake mechanisms. Nanovectors with a mean particle size between 94 and 348 nm and a positive superficial charge were formulated as eye drops containing 1% (w/v) of polyvinyl alcohol (PVA) with 7.1–7.5 pH. After three days of topical administration to mice, all formulations produced GFP in the corneal epithelium of mice. SLNs allowed the obtaining of a higher transfection efficiency than naked mRNA. All formulations produce IL-10, and the interleukin was even observed in the deeper layers of the epithelium of mice depending on the formulation. This work shows the potential application of mRNA-SLN-based nanosystems to address corneal inflammation by gene augmentation therapy.

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Nucleic Acid Delivery by Solid Lipid Nanoparticles Containing Switchable Lipids: Plasmid DNA vs. Messenger RNA

Cited by 37 publications

References 42 publications

Development of Peptide-Based Nanoparticles for Mitochondrial Plasmid DNA Delivery

Development of Peptide-Based Nanoparticles for Mitochondrial Plasmid DNA Delivery

α-Galactosidase A Augmentation by Non-Viral Gene Therapy: Evaluation in Fabry Disease Mice

mRNA-Based Nanomedicinal Products to Address Corneal Inflammation by Interleukin-10 Supplementation

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