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1.
Mol Pharm ; 20(4): 2039-2052, 2023 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-36848493

RESUMO

For over two decades, nanomaterials have been employed to facilitate intracellular delivery of small interfering RNA (siRNA), both in vitro and in vivo, to induce post-transcriptional gene silencing (PTGS) via RNA interference. Besides PTGS, siRNAs are also capable of transcriptional gene silencing (TGS) or epigenetic silencing, which targets the gene promoter in the nucleus and prevents transcription via repressive epigenetic modifications. However, silencing efficiency is hampered by poor intracellular and nuclear delivery. Here, polyarginine-terminated multilayered particles are reported as a versatile system for the delivery of TGS-inducing siRNA to potently suppress virus transcription in HIV-infected cells. siRNA is complexed with multilayered particles formed by layer-by-layer assembly of poly(styrenesulfonate) and poly(arginine) and incubated with HIV-infected cell types, including primary cells. Using deconvolution microscopy, uptake of fluorescently labeled siRNA is observed in the nuclei of HIV-1 infected cells. Viral RNA and protein are measured to confirm functional virus silencing from siRNA delivered using particles 16 days post-treatment. This work extends conventional particle-enabled PTGS siRNA delivery to the TGS pathway and paves the way for future studies on particle-delivered siRNA for efficient TGS of various diseases and infections, including HIV.


Assuntos
Infecções por HIV , HIV-1 , Humanos , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , HIV-1/genética , HIV-1/metabolismo , Inativação Gênica , Interferência de RNA , Epigênese Genética/genética , Infecções por HIV/genética , Infecções por HIV/terapia
2.
Adv Healthc Mater ; 10(16): e2100574, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34170631

RESUMO

Bio-nanoscience research encompasses studies on the interactions of nanomaterials with biological structures or what is commonly referred to as the biointerface. Fundamental studies on the influence of nanomaterial properties, including size, shape, composition, and charge, on the interaction with the biointerface have been central in bio-nanoscience to assess nanomaterial efficacy and safety for a range of biomedical applications. However, the state of the cells, tissues, or biological models can also influence the behavior of nanomaterials at the biointerface and their intracellular processing. Focusing on the "bio" in bio-nano, this review discusses the impact of biological properties at the cellular, tissue, and whole organism level that influences nanomaterial behavior, including cell type, cell cycle, tumor physiology, and disease states. Understanding how the biological factors can be addressed or exploited to enhance nanomaterial accumulation and uptake can guide the design of better and suitable models to improve the outcomes of materials in nanomedicine.


Assuntos
Fatores Biológicos , Nanoestruturas , Transporte Biológico , Humanos , Nanomedicina
3.
ACS Nano ; 15(3): 3736-3753, 2021 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-33600163

RESUMO

T cells play an important role in immunity and repair and are implicated in diseases, including blood cancers, viral infections, and inflammation, making them attractive targets for the treatment and prevention of diseases. Over recent years, the advent of nanomedicine has shown an increase in studies that use nanoparticles as carriers to deliver therapeutic cargo to T cells for ex vivo and in vivo applications. Nanoparticle-based delivery has several advantages, including the ability to load and protect a variety of drugs, control drug release, improve drug pharmacokinetics and biodistribution, and site- or cell-specific targeting. However, the delivery of nanoparticles to T cells remains a major technological challenge, which is primarily due to the nonphagocytic nature of T cells. In this review, we discuss the physiological barriers to effective T cell targeting and describe the different approaches used to deliver cargo-loaded nanoparticles to T cells for the treatment of disease such as T cell lymphoma and human immunodeficiency virus (HIV). In particular, engineering strategies that aim to improve nanoparticle internalization by T cells, including ligand-based targeting, will be highlighted. These nanoparticle engineering approaches are expected to inspire the development of effective nanomaterials that can target or manipulate the function of T cells for the treatment of T cell-related diseases.


Assuntos
Nanopartículas , Linfócitos T , Sistemas de Liberação de Medicamentos , Humanos , Nanomedicina , Distribuição Tecidual
4.
Biomacromolecules ; 21(8): 3186-3196, 2020 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-32786674

RESUMO

Neurodegenerative diseases are generally characterized by a progressive loss of neuronal subpopulations, with no available cure to date. One of the main reasons for the limited clinical outcomes of new drug formulations is the lack of appropriate in vitro human cell models for research and validation. Stem cell technologies provide an opportunity to address this challenge by using patient-derived cells as a platform to test various drug formulations, including particle-based drug carriers. The therapeutic efficacy of drug delivery systems relies on efficient cellular uptake of the carrier and can be dependent on its size, shape, and surface chemistry. Although considerable efforts have been made to understand the effects of the physiochemical properties of particles on two-dimensional cell culture models, little is known of their effect in three-dimensional (3D) cell models of neurodegenerative diseases. Herein, we investigated the role of particle size (235-1000 nm), charge (cationic and anionic), and density (1.05 and 1.8 g cm-3) on the interactions of particles with human embryonic stem cell-derived 3D cell cultures of sensory neurons, called sensory neurospheres (sNSP). Templated layer-by-layer particles, with silica or polystyrene cores, and self-assembled glycogen/DNA polyplexes were used. Particles with sizes <280 nm effectively penetrated sNSP. Additionally, effective plasmid DNA delivery was observed up to 6 days post-transfection with glycogen/DNA polyplexes. The findings provide guidance in nanoparticle design for therapies aimed at neurodegenerative diseases, in particular Friedreich's ataxia, whereby sensory neurons are predominantly affected. They also demonstrate the application of 3D models of human sensory neurons in preclinical drug development.


Assuntos
Nanopartículas , Humanos , Neurônios , Tamanho da Partícula , Dióxido de Silício , Células-Tronco
5.
Biomater Sci ; 8(9): 2398-2403, 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32270790

RESUMO

Increasing frataxin protein levels through gene therapy is envisaged to improve therapeutic outcomes for patients with Friedreich's ataxia (FRDA). A non-viral strategy that uses submicrometer-sized multilayered particles to deliver frataxin-encoding plasmid DNA affords up to 27 000-fold increase in frataxin gene expression within 2 days in vitro in a stem cell-derived neuronal model of FRDA.


Assuntos
DNA/administração & dosagem , Ataxia de Friedreich , Proteínas de Ligação ao Ferro/genética , Modelos Biológicos , Plasmídeos , Células Receptoras Sensoriais/metabolismo , Linhagem Celular Tumoral , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Frataxina
6.
ACS Nano ; 13(10): 11653-11664, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31573181

RESUMO

The intracellular delivery of functional nanoparticles (NPs) and the release of therapeutic payloads at a target site are central issues for biomedical applications. However, the endosomal entrapment of NPs typically results in the degradation of active cargo, leading to poor therapeutic outcomes. Current advances to promote the endosomal escape of NPs largely involve the use of polycationic polymers and cell-penetrating peptides (CPPs), which both can suffer from potential toxicity and convoluted synthesis/conjugation processes. Herein, we report the use of metal-phenolic networks (MPNs) as versatile and nontoxic coatings to facilitate the escape of NPs from endo/lysosomal compartments. The MPNs, which were engineered from the polyphenol tannic acid and FeIII or AlIII, enabled the endosomal escape of both inorganic (mesoporous silica) and organic (polystyrene and melamine resin) NPs owing to the "proton-sponge effect" arising from the buffering capacity of MPNs. Postfunctionalization of the MPN-coated NPs with low-fouling polymers did not impair the endosomal escape, indicating the modular and generalizable nature of this approach. We envisage that the ease of fabrication, versatility, low cytotoxicity, and promising endosomal escape performance displayed by the MPN coatings offer opportunities for such coatings to be used for the efficient delivery of cytoplasm-targeted therapeutics using NPs.


Assuntos
Endossomos/química , Nanopartículas/química , Polímeros/química , Compostos Férricos/química , Lisossomos/química , Dióxido de Silício/química
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