Unravelling the interactions of biodegradable dendritic nucleic acid carriers and neural cells

Spencer, Ana Patrícia; Leiro, Victoria; Pêgo, Ana Paula

doi:10.1039/d2bm01114j

Cited by 4 publications

(1 citation statement)

References 39 publications

(75 reference statements)

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“…Primary mouse neuronal cortical cell cultures were prepared from the prefrontal cortex of E16.5 C57BL/6 mice embryos, as previously described. 36 Briefly, embryos were obtained by caesarean section of pregnant C57BL/6 mice euthanized by cervical dislocation. The isolated prefrontal cortex was digested with trypsin (1.5 mg mL −1 ), washed with HBSS containing 10% (v/v) heat inactivated FBS (56 °C, 30 min) and then washed only with HBSS to remove FBS.…”

Section: Methodsmentioning

confidence: 99%

Supramolecular presentation of bioinstructive peptides on soft multilayered nanobiomaterials stimulates neurite outgrowth

et al. 2023

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Section: Methodsmentioning

confidence: 99%

Supramolecular presentation of bioinstructive peptides on soft multilayered nanobiomaterials stimulates neurite outgrowth

et al. 2023

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Engineered chitosan-derived nanocarrier for efficient siRNA delivery to peripheral and central neurons

Spencer,

Vilaça,

Xavier

et al. 2024

Preprint

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Gene therapy using small interfering RNA (siRNA) holds promise for treating neurological disorders by silencing specific genes, such as the phosphatase and tensin homolog (PTEN) gene, which restricts axonal growth. Yet, delivering siRNA to neurons efficiently is challenging due to premature degradation and unspecific delivery. Chitosan-based delivery systems have shown great potential due to their well-established biocompatibility. However, their limited transfection efficiency and lack of neuronal tropism require further modification. Building on our previous successes with neuron-targeted DNA delivery using chitosan, a novel approach for siRNA delivery aimed at PTEN downregulation is proposed. This involves using thiolated trimethyl chitosan (TMCSH)-based siRNA nanoparticles functionalized with the neurotropic C-terminal fragment of the tetanus neurotoxin heavy chain (HC) for efficient delivery to both peripheral and central neurons. These polyplexes demonstrated suitable physicochemical properties, biocompatibility, and no adverse effects on neuronal electrophysiology. Diverse neuronal models, including 3Dex vivocultures and microfluidics, confirmed polyplexes’ efficiency and neurospecificity. HC targeting significantly enhanced nanoparticle neuronal binding, and live cell imaging revealed five times faster retrograde transport along axons. Furthermore, siRNA delivery targeting PTEN promoted axonal outgrowth in embryonic cortical neurons. Thus, these polyplexes represent a promising platform for siRNA delivery, offering potential for clinical translation and therapeutic applications.

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Unveiling the potential of neuron-targeted dendriplexes for siRNA delivery using a PNS-CNS-on-Chip

Spencer,

Xavier,

Guimarães

et al. 2024

Preprint

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Neurological disorders, a leading global cause of death, encompass conditions affecting the peripheral and central nervous systems (PNS and CNS, respectively). Limited axon regeneration is a significant challenge in these disorders, and it is linked to proteins like PTEN. RNA-based therapeutics, particularly siRNAs, hold potential for silencing these inhibitory pathways, but their clinical application is hindered by poor stability and cellular uptake. Our study addressed this challenge with the development of novel, fully biodegradable dendritic nanoparticles designed specifically for neuron targeting. These nanoparticles were functionalized with the neurotropic binding domain of tetanus toxin, enhancing selective neuronal targeting and cellular internalization. We demonstrated that these dendriplexes not only maintain biocompatibility and efficient siRNA delivery in neuronal cultures but also significantly enhance axonal growth, as shown in microfluidic models. In a groundbreaking PNS-CNS-on-Chip, dendriplexes exhibited effective migration from PNS to CNS neurons, highlighting their potential for targeted therapeutic delivery. This study pioneers the application of microfluidics to demonstrate the CNS targeting of dendriplexes, paving the way for innovative treatments in the field of nanomedicine.

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Unravelling the interactions of biodegradable dendritic nucleic acid carriers and neural cells

Abstract: Nanomedicine based on nanoparticles as carriers of therapeutics is expected to drastically influence the healthcare future. However, clinical translation of these technologies can be very challenging. The development process of...

Cited by 4 publications

References 39 publications

Supramolecular presentation of bioinstructive peptides on soft multilayered nanobiomaterials stimulates neurite outgrowth

Supramolecular presentation of bioinstructive peptides on soft multilayered nanobiomaterials stimulates neurite outgrowth

Engineered chitosan-derived nanocarrier for efficient siRNA delivery to peripheral and central neurons

Unveiling the potential of neuron-targeted dendriplexes for siRNA delivery using a PNS-CNS-on-Chip

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