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1.
Med Hypotheses ; 143: 110203, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33017912

RESUMO

MicroRNAs (miRNAs) naturally occur in plants and all living organisms. They play an important role in gene regulation through binding toa specific region in open reading frames (ORFs) and/or untranslated regions (UTRs) to block the translation processes through either degrading or blocking mRNA resulting in knocking down or suppression of targeted genes. Plants and many organisms protect themselves from viruses through the production of miRNAs, which are complementary to 3UTR of viruses resulting in degrading the viral mRNA or block the translation on ribosomes. As pandemic, COVID-19, and its consequences on the global economy, we hypothesized a new approach for the treatment of COVID-19 paints. This approach includes designing a mix of miRNAs targeting several regions on COVID-19 open reading frame (ORF) and 3 UTR and suitable delivery system targeting respiratory system tissues. These synthesized miRNAs may be delivered to humansinnon-viral delivery systems such as liposomes like exosome (extracellular vesicle), polymer-based carriers, or inorganic nanoparticles, which are considered to be more suitable for human use.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/terapia , MicroRNAs/uso terapêutico , Pneumonia Viral/terapia , Regiões 3' não Traduzidas , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Sistemas de Liberação de Medicamentos , Exossomos , Regulação da Expressão Gênica , Técnicas de Transferência de Genes , Genoma Viral , Humanos , Lipossomos/química , Nanopartículas/química , Fases de Leitura Aberta , Pandemias , Pneumonia Viral/virologia , Polímeros/química
2.
J Biomed Nanotechnol ; 16(5): 553-582, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32919478

RESUMO

Successful gene therapy depends on the design of effective gene delivery systems. A gene delivery system is considered a powerful tool for the release of genetic material within cells resulting in a change in cell functions and protein production. The release of genes in a controlled manner by using appropriate carriers facilitates their release without side effects and increases the expression of genes at the released site. It is expected that significant changes in the combination of several genes and drugs can be provided by developing treatment systems sensitive to different stimuli such as redox potential, pH variations, temperature gradients, light irradiation, and enzyme activity. The most important advantages for the release of genes and stimuli-responsive therapeutics include delivering vectors locally, reducing side effects and causing no toxicity to distant tissues while at the same time reducing the immune response to the vectors. In this review, we aim to discuss different types of gene carriers involved in the controlled transfer of nucleic acids (non-viral inorganic and organic nanoparticles (NPs) and virus-like particles (VLPs)) as well as the simultaneous transfer of several genes and/or drugs into cells or different tissues, providing for an efficient and safe treatment of numerous diseases.


Assuntos
Nanoestruturas , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Técnicas de Transferência de Genes , Nanopartículas
3.
Am J Bioeth ; 20(8): 23-25, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32804062
4.
Am J Bioeth ; 20(8): 21-23, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32804064
6.
PLoS One ; 15(8): e0237156, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32780756

RESUMO

Ischemic neuropathy is common in subjects with critical limb ischemia, frequently causing chronic neuropathic pain. However, neuropathic pain caused by ischemia is hard to control despite the restoration of an adequate blood flow. Here, we used a rat model of ischemic-reperfusion nerve injury (IRI) to investigate possible effects of hepatocyte growth factor (HGF) against ischemic neuropathy. Hemagglutinating virus of Japan (HVJ) liposomes containing plasmids encoded with HGF was delivered into the peripheral nervous system by retrograde axonal transport following its repeated injections into the tibialis anterior muscle in the right hindlimb. First HGF gene transfer was done immediately after IRI, and repeated at 1, 2 and 3 weeks later. Rats with IRI exhibited pronounced mechanical allodynia and thermal hyperalgesia, decreased blood flow and skin temperature, and lowered thresholds of plantar stimuli in the hind paw. These were all significantly improved by HGF gene transfer, as also were sciatic nerve conduction velocity and muscle action potential amplitudes. Histologically, HGF gene transfer resulted in a significant increase of endoneurial microvessels in sciatic and tibial nerves and promoted nerve regeneration which were confirmed by morphometric analysis. Neovascularization was observed in the contralateral side of peripheral nerves as well. In addition, IRI elevated mRNA levels of P2X3 and P2Y1 receptors, and transient receptor potential vanilloid receptor subtype 1 (TRPV1) in sciatic nerves, dorsal root ganglia and spinal cord, and these elevated levels were inhibited by HGF gene transfer. In conclusion, HGF gene transfer is a potent candidate for treatment of acute ischemic neuropathy caused by reperfusion injury, because of robust angiogenesis and enhanced nerve regeneration.


Assuntos
Terapia Genética/métodos , Fator de Crescimento de Hepatócito/genética , Neuralgia/terapia , Traumatismo por Reperfusão/terapia , Animais , Modelos Animais de Doenças , Gânglios Espinais/metabolismo , Técnicas de Transferência de Genes , Vetores Genéticos , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Hiperalgesia/metabolismo , Lipossomos/metabolismo , Masculino , Ratos , Ratos Wistar , Nervo Isquiático/metabolismo , Vírus Sendai/genética , Resultado do Tratamento
7.
PLoS One ; 15(7): e0236788, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32735629

RESUMO

This study aimed to establish and reproduce transgenic pigs expressing human growth hormone (hGH) in their milk. We also aimed to purify hGH from the milk, to characterize the purified protein, and to assess the potential of our model for mass production of therapeutic proteins using transgenic techniques. Using ~15.5 L transgenic pig milk, we obtained proteins with ≥ 99% purity after three pre-treatments and five column chromatography steps. To confirm the biosimilarity of our milk-derived purified recombinant hGH (CGH942) with commercially available somatropin (Genotropin), we performed spectroscopy, structural, and biological analyses. We observed no difference between the purified protein and Genotropin samples. Furthermore, rat models were used to assess growth promotion potential. Our results indicate that CGH942 promotes growth, by increasing bone development and body weight. Toxicity assessments revealed no abnormal findings after 4 weeks of continuous administration and 2 weeks of recovery. The no-observed-adverse-effect level for both males and females was determined to be 0.6 mg/kg/day. Thus, no toxicological differences were observed between commercially available somatropin and CGH942 obtained from transgenic pig milk. In conclusion, we describe a transgenic technique using pigs, providing a new platform to produce human therapeutic proteins.


Assuntos
Animais Geneticamente Modificados/metabolismo , Hormônio do Crescimento Humano , Proteínas Recombinantes , Animais , Cromatografia de Afinidade , Feminino , Técnicas de Transferência de Genes , Hormônio do Crescimento Humano/química , Hormônio do Crescimento Humano/genética , Hormônio do Crescimento Humano/metabolismo , Humanos , Ratos , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/toxicidade , Suínos
8.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 49(1): 20-34, 2020 May 25.
Artigo em Chinês | MEDLINE | ID: mdl-32621413

RESUMO

Mesenchymal stem cells (MSCs) have the inherent tumor-homing ability with the attraction of multiple chemokines released by tumor tissues or tumor microenvironments, which can be utilized as promising cellular carriers for targeted delivery of anti-tumor drugs and genes. In most circumstances, large amount of systemicly administrated MSCs will be firstly trapped by lungs, following with re-distribution and homing to tumor tissues after lung clearance. Several approaches like enhanced interactions between chemokines and receptors on MSCs or reducing the retention of MSCs by changes of administration methods are firstly reviewed for improving the homing of MSCs towards tumor tissues. Additionally, the potentials and gains of utilizing MSCs to carry several chemotherapeutics, such as doxorubicin, paclitaxel and gemcitabine are summarized, showing the advantages of overcoming the short half-life and poor tumor targeting of these chemotherapeutics. Moreover, the applications of MSCs to protect and deliver therapeutic genes to tumor sites for selectively tumor cells eliminating or promoting immune system are highlighted. In addition, the potentials of using MSCs for tumor-targeting delivery of diagnostic and therapeutic agents are addressed. We believed that the continuous improvement and optimization of this stem cells-based cellular delivery system will provide a novel delivery strategy and option for tumor treatment.


Assuntos
Antineoplásicos , Sistemas de Liberação de Medicamentos , Técnicas de Transferência de Genes , Células-Tronco Mesenquimais , Neoplasias , Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Humanos , Neoplasias/terapia , Paclitaxel/administração & dosagem , Pesquisa/tendências
9.
Int J Nanomedicine ; 15: 4237-4256, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606675

RESUMO

With the passage of time and more advanced societies, there is a greater emergence and incidence of disease and necessity for improved treatments. In this respect, nowadays, aptamers, with their better efficiency at diagnosing and treating diseases than antibodies, are at the center of attention. Here, in this review, we first investigate aptamer function in various fields (such as the detection and remedy of pathogens, modification of nanoparticles, antibiotic delivery and gene delivery). Then, we present aptamer-conjugated nanocomplexes as the main and efficient factor in gene delivery. Finally, we focus on the targeted co-delivery of genes and drugs by nanocomplexes, as a new exciting approach for cancer treatment in the decades ahead to meet our growing societal needs.


Assuntos
Antibacterianos/farmacologia , Aptâmeros de Nucleotídeos/química , Técnicas de Transferência de Genes , Nanopartículas/química , Sistemas de Liberação de Medicamentos , Humanos , Nanopartículas/ultraestrutura , Polietilenoimina/química
11.
Int J Nanomedicine ; 15: 3639-3647, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32547019

RESUMO

Purpose: Astrocyte dysfunction is a hallmark of central nervous system injury or infection. As a primary contributor to neurodegeneration, astrocytes are an ideal therapeutic target to combat neurodegenerative conditions. Gene therapy has arisen as an innovative technique that provides excellent prospect for disease intervention. Poly (lactide-co-glycolide) (PLGA) and polyethylenimine (PEI) are polymeric nanoparticles commonly used in gene delivery, each manifesting their own set of advantages and disadvantages. As a clinically approved polymer by the Federal Drug Administration, well characterized for its biodegradability and biocompatibility, PLGA-based nanoparticles (PLGA-NPs) are appealing for translational gene delivery systems. However, our investigations revealed PLGA-NPs were ineffective at facilitating exogenous gene expression in primary human astrocytes, despite their success in other cell lines. Furthermore, PEI polymers illustrate high delivery efficiency but induce cytotoxicity. The purpose of this study is to develop viable and biocompatible NPsystem for astrocyte-targeted gene therapy. Materials and Methods: Successful gene expression by PLGA-NPs alone or in combination with arginine-modified PEI polymers (AnPn) was assessed by a luciferase reporter gene encapsulated in PLGA-NPs. Cytoplasmic release and nuclear localization of DNA were investigated using fluorescent confocal imaging with YOYO-labeled plasmid DNA (pDNA). NP-mediated cytotoxicity was assessed via lactate dehydrogenase in primary human astrocytes and neurons. Results: Confocal imaging of YOYO-labeled pDNA confirmed PLGA-NPs delivered pDNA to the cytoplasm in a dose and time-dependent manner. However, co-staining revealed pDNA delivered by PLGA-NPs did not localize to the nucleus. The addition of AnPn significantly improved nuclear localization of pDNA and successfully achieved gene expression in primary human astrocytes. Moreover, these formulations were biocompatible with both astrocytes and neurons. Conclusion: By co-transfecting two polymeric NPs, we developed an improved system for gene delivery and expression in primary human astrocytes. These findings provide a basis for a biocompatible and clinically translatable method to regulate astrocyte function during neurodegenerative diseases and disorders.


Assuntos
Arginina/química , Astrócitos/metabolismo , Técnicas de Transferência de Genes , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , DNA/genética , Células HEK293 , Humanos , Tamanho da Partícula , Plasmídeos/genética , Polietilenoimina , Transfecção
12.
Nat Commun ; 11(1): 3034, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32541663

RESUMO

Alphaproteobacteria, which are the most abundant microorganisms of temperate oceans, produce phage-like particles called gene transfer agents (GTAs) that mediate lateral gene exchange. However, the mechanism by which GTAs deliver DNA into cells is unknown. Here we present the structure of the GTA of Rhodobacter capsulatus (RcGTA) and describe the conformational changes required for its DNA ejection. The structure of RcGTA resembles that of a tailed phage, but it has an oblate head shortened in the direction of the tail axis, which limits its packaging capacity to less than 4,500 base pairs of linear double-stranded DNA. The tail channel of RcGTA contains a trimer of proteins that possess features of both tape measure proteins of long-tailed phages from the family Siphoviridae and tail needle proteins of short-tailed phages from the family Podoviridae. The opening of a constriction within the RcGTA baseplate enables the ejection of DNA into bacterial periplasm.


Assuntos
Bacteriófagos/fisiologia , Técnicas de Transferência de Genes , Rhodobacter capsulatus/genética , Rhodobacter capsulatus/virologia , Siphoviridae/fisiologia , Bacteriófagos/genética , Bacteriófagos/ultraestrutura , Microscopia Crioeletrônica , DNA Bacteriano/genética , Regulação Bacteriana da Expressão Gênica , Transferência Genética Horizontal , Siphoviridae/genética , Siphoviridae/ultraestrutura
13.
Nat Commun ; 11(1): 3253, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32591505

RESUMO

Optogenetics has become an indispensable tool for investigating brain functions. Although non-human primates are particularly useful models for understanding the functions and dysfunctions of the human brain, application of optogenetics to non-human primates is still limited. In the present study, we generate an effective adeno-associated viral vector serotype DJ to express channelrhodopsin-2 (ChR2) under the control of a strong ubiquitous CAG promoter and inject into the somatotopically identified forelimb region of the primary motor cortex in macaque monkeys. ChR2 is strongly expressed around the injection sites, and optogenetic intracortical microstimulation (oICMS) through a homemade optrode induces prominent cortical activity: Even single-pulse, short-duration oICMS evokes long-lasting repetitive firings of cortical neurons. In addition, oICMS elicits distinct forelimb movements and muscle activity, which are comparable to those elicited by conventional electrical ICMS. The present study removes obstacles to optogenetic manipulation of neuronal activity and behaviors in non-human primates.


Assuntos
Membro Anterior/fisiologia , Córtex Motor/fisiologia , Movimento/fisiologia , Optogenética , Animais , Channelrhodopsins/metabolismo , Dependovirus/genética , Técnicas de Transferência de Genes , Vetores Genéticos/metabolismo , Macaca , Neurônios/fisiologia , Estimulação Física
14.
Transl Res ; 223: 89-106, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32522669

RESUMO

Extensive antibiotic use combined with poor historical drug stewardship practices have created a medical crisis in which once treatable bacterial infections are now increasingly unmanageable. To combat this, new antibiotics will need to be developed and safeguarded. An emerging class of antibiotics based upon nuclease-stable antisense technologies has proven valuable in preclinical testing against a variety of bacterial pathogens. This review describes the current state of development of antisense-based antibiotics, the mechanisms thus far employed by these compounds, and possible future avenues of research.


Assuntos
Antibacterianos/farmacologia , Animais , Bactérias/efeitos dos fármacos , Resistência Microbiana a Medicamentos/efeitos dos fármacos , Resistência Microbiana a Medicamentos/genética , Técnicas de Transferência de Genes , Humanos , RNA Antissenso/química , RNA Antissenso/farmacologia
16.
Proc Natl Acad Sci U S A ; 117(20): 10976-10982, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32358194

RESUMO

Advances in gene editing are leading to new medical interventions where patients' own cells are used for stem cell therapies and immunotherapies. One of the key limitations to translating these treatments to the clinic is the need for scalable technologies for engineering cells efficiently and safely. Toward this goal, microfluidic strategies to induce membrane pores and permeability have emerged as promising techniques to deliver biomolecular cargo into cells. As these technologies continue to mature, there is a need to achieve efficient, safe, nontoxic, fast, and economical processing of clinically relevant cell types. We demonstrate an acoustofluidic sonoporation method to deliver plasmids to immortalized and primary human cell types, based on pore formation and permeabilization of cell membranes with acoustic waves. This acoustofluidic-mediated approach achieves fast and efficient intracellular delivery of an enhanced green fluorescent protein-expressing plasmid to cells at a scalable throughput of 200,000 cells/min in a single channel. Analyses of intracellular delivery and nuclear membrane rupture revealed mechanisms underlying acoustofluidic delivery and successful gene expression. Our studies show that acoustofluidic technologies are promising platforms for gene delivery and a useful tool for investigating membrane repair.


Assuntos
Técnicas de Transferência de Genes , Terapia Genética/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Sistema Hematopoético , Células-Tronco , Sobrevivência Celular , Citoplasma , Expressão Gênica , Técnicas de Transferência de Genes/instrumentação , Terapia Genética/instrumentação , Proteínas de Fluorescência Verde/genética , Humanos , Células Jurkat , Plasmídeos , Som
18.
Int J Nanomedicine ; 15: 2809-2828, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32368056

RESUMO

Introduction: Glioblastoma (GBM) is the most common and lethal of the central nervous system (CNS) malignancies. The initiation, progression, and infiltration ability of GBMs are attributed in part to the dysregulation of microRNAs (miRNAs). Thus, targeting dysregulated miRNAs with RNA oligonucleotides (RNA interference, RNAi) has been proposed for GBM treatment. Despite promising results in the laboratory, RNA oligonucleotides have clinical limitations that include poor RNA stability and off-target effects. RNAi therapies against GBM confront an additional obstacle, as they need to cross the blood-brain barrier (BBB). Methods: Here, we developed gold-liposome nanoparticles conjugated with the brain targeting peptides apolipoprotein E (ApoE) and rabies virus glycoprotein (RVG). First, we functionalized gold nanoparticles with oligonucleotide miRNA inhibitors (OMIs), creating spherical nucleic acids (SNAs). Next, we encapsulated SNAs into ApoE, or RVG-conjugated liposomes, to obtain SNA-Liposome-ApoE and SNA-Liposome-RVG, respectively. We characterized each nanoparticle in terms of their size, charge, encapsulation efficiency, and delivery efficiency into U87 GBM cells in vitro. Then, they were administered intravenously (iv) in GBM syngeneic mice to evaluate their delivery efficiency to brain tumor tissue. Results: SNA-Liposomes of about 30-50 nm in diameter internalized U87 GBM cells and inhibited the expression of miRNA-92b, an aberrantly overexpressed miRNA in GBM cell lines and GBM tumors. Conjugating SNA-Liposomes with ApoE or RVG peptides increased their systemic delivery to the brain tumors of GBM syngeneic mice. SNA-Liposome-ApoE demonstrated to accumulate at higher extension in brain tumor tissues, when compared with non-treated controls, SNA-Liposomes, or SNA-Liposome-RVG. Discussion: SNA-Liposome-ApoE has the potential to advance the translation of miRNA-based therapies for GBM as well as other CNS disorders.


Assuntos
Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Lipossomos/administração & dosagem , Interferência de RNA , Animais , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Técnicas de Transferência de Genes , Glioblastoma/genética , Glioblastoma/patologia , Ouro/química , Humanos , Lipossomos/química , Masculino , Nanopartículas Metálicas/química , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Ácidos Nucleicos/química , Oligonucleotídeos/química , Oligonucleotídeos/genética , Oligonucleotídeos/farmacocinética , Proteínas do Envelope Viral/genética , Ensaios Antitumorais Modelo de Xenoenxerto
19.
PLoS One ; 15(5): e0234073, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32470062

RESUMO

Craniosynostosis is the premature fusion of cranial bones. The goal of this study was to determine if delivery of recombinant tissue nonspecific alkaline phosphatase (TNAP) could prevent or diminish the severity of craniosynostosis in a C57BL/6 FGFR2C342Y/+ model of neonatal onset craniosynostosis or a BALB/c FGFR2C342Y/+ model of postnatal onset craniosynostosis. Mice were injected with a lentivirus encoding a mineral targeted form of TNAP immediately after birth. Cranial bone fusion as well as cranial bone volume, mineral content and density were assessed by micro CT. Craniofacial shape was measured with calipers. Alkaline phosphatase, alanine amino transferase (ALT) and aspartate amino transferase (AST) activity levels were measured in serum. Neonatal delivery of TNAP diminished craniosynostosis severity from 94% suture obliteration in vehicle treated mice to 67% suture obliteration in treated mice, p<0.02) and the incidence of malocclusion from 82.4% to 34.7% (p<0.03), with no effect on cranial bone in C57BL/6 FGFR2C342Y/+ mice. In contrast, treatment with TNAP increased cranial bone volume (p< 0.01), density (p< 0.01) and mineral content (p< 0.01) as compared to vehicle treated controls, but had no effect on craniosynostosis or malocclusion in BALB/c FGFR2C342Y/+ mice. These results indicate that postnatal recombinant TNAP enzyme therapy diminishes craniosynostosis severity in the C57BL/6 FGFR2C342Y/+ neonatal onset mouse model of Crouzon syndrome, and that effects of exogenous TNAP are genetic background dependent.


Assuntos
Fosfatase Alcalina/genética , Disostose Craniofacial/terapia , Craniossinostoses/terapia , Técnicas de Transferência de Genes , Fosfatase Alcalina/sangue , Animais , Animais Recém-Nascidos , Peso Corporal , Densidade Óssea , Suturas Cranianas/patologia , Disostose Craniofacial/diagnóstico por imagem , Craniossinostoses/diagnóstico por imagem , Modelos Animais de Doenças , Fígado/enzimologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Tamanho do Órgão , Microtomografia por Raio-X
20.
Artigo em Inglês | MEDLINE | ID: mdl-32375002

RESUMO

Lipid nanoparticle (LNP) packaged mRNA vaccines have been deployed against infectious diseases such as COVID-19, yet their structural features remain unclear. Cholesterol, a major constituent within LNPs, contributes to their morphology that influences gene delivery. Herein, we examine the structure of LNPs containing cholesterol derivatives using electron microscopy, differential scanning calorimetry, and membrane fluidity assays. LNPs formulated with C24 alkyl derivatives of cholesterol show a polymorphic shape and various degrees of multilamellarity and lipid partitioning, likely due to phase separation. The addition of methyl and ethyl groups to the C24 alkyl tail of the cholesterol backbone induces multilamellarity (>50% increase compared to cholesterol), while the addition of a double bond induces lipid partitioning (>90% increase compared to cholesterol). LNPs with multilamellar and faceted structures, as well as a lamellar lipid phase, showed higher gene transfection. Unraveling the structure of mRNA-LNPs can enable their rational design toward enhanced gene delivery.


Assuntos
Colesterol/análogos & derivados , Infecções por Coronavirus/prevenção & controle , Portadores de Fármacos/química , Nanopartículas/química , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , RNA Mensageiro/administração & dosagem , Vacinas Virais/administração & dosagem , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/genética , Técnicas de Transferência de Genes , Células HeLa , Humanos , Lipídeos/química , Nanopartículas/ultraestrutura , Transição de Fase , Fitosteróis/química , RNA Mensageiro/genética , Transfecção , Vacinas Virais/genética
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