RESUMEN
We introduce a two-pronged strategy comprising focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening and long-circulating biodegradable nanoparticles (NPs) for systemic delivery of nucleic acids to the brain. Biodegradable poly(ß-amino ester) polymer-based NPs were engineered to stably package various types of nucleic acid payloads and enable prolonged systemic circulation while retaining excellent serum stability. FUS was applied to a predetermined coordinate within the brain to transiently open the BBB, thereby allowing the systemically administered long-circulating NPs to traverse the BBB and accumulate in the FUS-treated brain region, where plasmid DNA or mRNA payloads produced reporter proteins in astrocytes and neurons. In contrast, poorly circulating and/or serum-unstable NPs, including the lipid NP analogous to a platform used in clinic, were unable to provide efficient nucleic acid delivery to the brain regardless of the BBB-opening FUS. The marriage of FUS-mediated BBB opening and the long-circulating NPs engineered to copackage mRNA encoding CRISPR-associated protein 9 and single-guide RNA resulted in genome editing in astrocytes and neurons precisely in the FUS-treated brain region. The combined delivery strategy provides a versatile means to achieve efficient and site-specific therapeutic nucleic acid delivery to and genome editing in the brain via a systemic route.
Asunto(s)
Barrera Hematoencefálica , Edición Génica , Nanopartículas , Barrera Hematoencefálica/metabolismo , Nanopartículas/química , Animales , Edición Génica/métodos , Encéfalo/metabolismo , Ratones , Ondas Ultrasónicas , Astrocitos/metabolismo , ADN/química , ADN/administración & dosificación , Polímeros/química , ARN Mensajero/metabolismo , ARN Mensajero/genética , Neuronas/metabolismo , Técnicas de Transferencia de Gen , Plásmidos/administración & dosificación , Plásmidos/genética , Ácidos Nucleicos/química , Ácidos Nucleicos/administración & dosificación , Ácidos Nucleicos/metabolismo , HumanosRESUMEN
RNA is a promising nucleic acid-based biomolecule for various treatments because of its high efficacy, low toxicity, and the tremendous availability of targeting sequences. Nevertheless, RNA shows instability and has a short half-life in physiological environments such as the bloodstream in the presence of RNAase. Therefore, developing reliable delivery strategies is important for targeting disease sites and maximizing the therapeutic effect of RNA drugs, particularly in the field of immunotherapy. In this mini-review, we highlight two major approaches: (1) delivery vehicles and (2) chemical modifications. Recent advances in delivery vehicles employ nanotechnologies such as lipid-based nanoparticles, viral vectors, and inorganic nanocarriers to precisely target specific cell types to facilitate RNA cellular entry. On the other hand, chemical modification utilizes the alteration of RNA structures via the addition of covalent bonds such as N-acetylgalactosamine or antibodies (antibody-oligonucleotide conjugates) to target specific receptors of cells. The pros and cons of these technologies are enlisted in this review. We aim to review nucleic acid drugs, their delivery systems, targeting strategies, and related chemical modifications. Finally, we express our perspective on the potential combination of RNA-based click chemistry with adoptive cell therapy (e.g., B cells or T cells) to address the issues of short duration and short half-life associated with antibody-oligonucleotide conjugate drugs.
Asunto(s)
Sistemas de Liberación de Medicamentos , Inmunoterapia , ARN , Humanos , Inmunoterapia/métodos , Sistemas de Liberación de Medicamentos/métodos , Animales , Nanopartículas/química , Ácidos Nucleicos/administración & dosificación , Ácidos Nucleicos/químicaRESUMEN
In recent years, gene therapy has been made possible with the success of nucleic acid drugs against sepsis and its related organ dysfunction. Therapeutics based on nucleic acids such as small interfering RNAs (siRNAs), microRNAs (miRNAs), messenger RNAs (mRNAs), and plasmid DNAs (pDNAs) guarantee to treat previously undruggable diseases. The advantage of nucleic acid-based therapy against sepsis lies in the development of nanocarriers, achieving targeted and controlled gene delivery for improved efficacy with minimal adverse effects. Entrapment into nanocarriers also ameliorates the poor cellular uptake of naked nucleic acids. In this study, we discuss the current state of the art in nanoparticles for nucleic acid delivery to treat hyperinflammation and apoptosis associated with sepsis. The optimized design of the nanoparticles through physicochemical property modification and ligand conjugation can target specific organs-such as lung, heart, kidney, and liver-to mitigate multiple sepsis-associated organ injuries. This review highlights the nanomaterials designed for fabricating the anti-sepsis nanosystems, their physicochemical characterization, the mechanisms of nucleic acid-based therapy in working against sepsis, and the potential for promoting the therapeutic efficiency of the nucleic acids. The current investigations associated with nanoparticulate nucleic acid application in sepsis management are summarized in this paper. Noteworthily, the potential application of nanotherapeutic nucleic acids allows for a novel strategy to treat sepsis. Further clinical studies are required to confirm the findings in cell- and animal-based experiments. The capability of large-scale production and reproducibility of nanoparticle products are also critical for commercialization. It is expected that numerous anti-sepsis possibilities will be investigated for nucleic acid-based nanotherapeutics in the future.
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Nanopartículas , Ácidos Nucleicos , Sepsis , Sepsis/tratamiento farmacológico , Sepsis/terapia , Humanos , Ácidos Nucleicos/uso terapéutico , Ácidos Nucleicos/administración & dosificación , Animales , Nanopartículas/química , Terapia Genética/métodos , Insuficiencia Multiorgánica/terapia , Insuficiencia Multiorgánica/tratamiento farmacológico , Técnicas de Transferencia de GenRESUMEN
Lipid nanoparticles (LNPs) are the most clinically advanced drug delivery system for nucleic acid therapeutics, exemplified by the success of the COVID-19 mRNA vaccines. However, their clinical use is currently limited to hepatic diseases and vaccines due to their tendency to accumulate in the liver upon intravenous administration. To fully leverage their potential, it is essential to understand and address their liver tropism, while also developing strategies to enhance delivery to tissues beyond the liver. Ensuring that these therapeutics reach their target cells while avoiding off-target cells is essential for both their efficacy and safety. There are three potential targeting strategies-passive, active, and endogenous-which can be used individually or in combination to target nonhepatic tissues. In this review, we delve into the recent advancements in LNP engineering for delivering nucleic acid beyond the liver.
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Lípidos , Hígado , Nanopartículas , Ácidos Nucleicos , Humanos , Nanopartículas/química , Hígado/metabolismo , Lípidos/química , Ácidos Nucleicos/administración & dosificación , SARS-CoV-2 , Sistemas de Liberación de Medicamentos , COVID-19/virología , Animales , Técnicas de Transferencia de Gen , Vacunas contra la COVID-19/administración & dosificación , LiposomasRESUMEN
Nucleic acid (NA)-based therapies are revolutionizing biomedical research through their ability to control cellular functions at the genetic level. This work demonstrates a versatile elastin-like polypeptide (ELP) carrier system using a layer-by-layer (LbL) formulation approach that delivers NA cargos ranging in size from siRNA to plasmids. The components of the system can be reconfigured to modulate the biochemical and biophysical characteristics of the carrier for engaging the unique features of the biological target. We show the physical characterization and biological performance of LbL ELP nucleic acid nanoparticles (LENNs) in murine and human bladder tumor cell lines. Targeting bladder tumors is difficult owing to the constant influx of urine into the bladder, leading to low contact times (typically <2 h) for therapeutic agents delivered via intravesical instillation. LENN complexes bind to bladder tumor cells within 30 min and become rapidly internalized to release their NA cargo within 60 min. Our data show that a readily adaptable NA-delivery system has been created that is flexible in its targeting ability, cargo size, and disassembly kinetics. This approach provides an alternative path to either lipid nanoparticle formulations that suffer from inefficiency and physicochemical instability or viral vectors that are plagued by manufacturing and immune rejection challenges. This agile ELP-based nanocarrier provides an alternative route for nucleic acid delivery using a biomanufacturable, biodegradable, biocompatible, and highly tunable vehicle capable of targeting cells via engagement with overexpressed cell surface receptors.
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Elastina , Nanopartículas , Neoplasias de la Vejiga Urinaria , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Humanos , Elastina/química , Ratones , Animales , Nanopartículas/química , Línea Celular Tumoral , Receptores ErbB/metabolismo , Receptores ErbB/genética , Péptidos/química , Ácidos Nucleicos/química , Ácidos Nucleicos/administración & dosificación , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/química , Polipéptidos Similares a ElastinaRESUMEN
Cancer has emerged as a significant threat to human health. Nucleic acid therapeutics regulate the gene expression process by introducing exogenous nucleic acid fragments, offering new possibilities for tumor remission and even cure. Their mechanism of action and high specificity demonstrate great potential in cancer treatment. However, nucleic acid drugs face challenges such as low stability and limited ability to cross physiological barriers in vivo. To address these issues, various nucleic acid delivery vectors have been developed to enhance the stability and facilitate precise targeted delivery of nucleic acid drugs within the body. In this review article, we primarily introduce the structures and principles of nucleic acid drugs commonly used in cancer therapy, as well as their cellular uptake and intracellular transportation processes. We focus on the various vectors commonly employed in nucleic acid drug delivery, highlighting their research progress and applications in recent years. Furthermore, we propose potential trends and prospects of nucleic acid drugs and their carriers in the future.
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Sistemas de Liberación de Medicamentos , Neoplasias , Ácidos Nucleicos , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Ácidos Nucleicos/administración & dosificación , Ácidos Nucleicos/uso terapéutico , Ácidos Nucleicos/química , Portadores de Fármacos/química , Antineoplásicos/uso terapéutico , Antineoplásicos/administración & dosificaciónRESUMEN
Delivery of genetic information to the interior of target cells in vivo has been a major challenge facing gene therapies. This barrier is now being overcome, owing in part to dramatic advances made by lipid-based systems that have led to lipid nanoparticles (LNPs) that enable delivery of nucleic acid-based vaccines and therapeutics. Examples include the clinically approved COVID-19 LNP mRNA vaccines and Onpattro (patisiran), an LNP small interfering RNA therapeutic to treat transthyretin-induced amyloidosis (hATTR). In addition, a host of promising LNP-enabled vaccines and gene therapies are in clinical development. Here, we trace this success to two streams of research conducted over the past 60 years: the discovery of the transfection properties of lipoplexes composed of positively charged cationic lipids complexed with nucleic acid cargos and the development of lipid nanoparticles using ionizable cationic lipids. The fundamental insights gained from these two streams of research offer potential delivery solutions for most forms of gene therapies.
Asunto(s)
Terapia Genética , Lípidos , Nanopartículas , Nanopartículas/química , Humanos , Lípidos/química , Terapia Genética/métodos , Ácidos Nucleicos/administración & dosificación , Animales , Técnicas de Transferencia de Gen , ARN Interferente Pequeño/administración & dosificación , Vacunas contra la COVID-19/administración & dosificación , COVID-19 , LiposomasRESUMEN
Chemotherapy is the main treatment for bladder cancer, but drug resistance and side effects limit its application and therapeutic effect. Herein, we constructed doxorubicin (DOX)/COOH-mesoporous silica nanoparticle/polyethylenimine (PEI)/nucleic acid chimeras (DOX/MSN/Chimeras) to reduce the toxicity of chemotherapy drugs and the resistance of bladder cancer cells. Transmission electron microscopy showed that PEI was coated on the DOX/MSN/BSA nanoparticles with a diameter of about 150â¯nm. DOX/MSN/PEI could control DOX release for over 48â¯h, and the sudden release rate was significantly lower than DOX/MSN. Immunohistochemical results showed that DOX/MSN/Chimera specifically bound to bladder cancer cells, and markedly inhibited PI3K expression and proliferation of DOX-resistant bladder cancer cells. DOX/MSN/Chimera promoted the apoptosis of drug-resistant bladder cancer cells, which was superior to DOX/MSN/Aptamer or DOX/MSN. We further carried out animal experiments and found that DOX/MSN/Chimera could reduce the volume of transplanted tumors in vivo. Compared with DOX/MSN/Aptamer group, the proliferation rate was significantly decreased and the proportion of apoptotic cells was highly increased. Through the histological observation of kidneys and lungs, we believed that DOX/MSN/Chimera can effectively reduce the damage of chemotherapy drugs to normal tissues. In conclusion, we constructed a COOH-MSN/nucleic acid chimera conjugate for the targeted delivery of siRNA and anti-cancer drugs. Our study provides a new method for personalized and targeted treatment of drug-resistant bladder cancer.
Asunto(s)
Doxorrubicina , Resistencia a Antineoplásicos , Ratones Desnudos , Nanopartículas , ARN Interferente Pequeño , Dióxido de Silicio , Neoplasias de la Vejiga Urinaria , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/genética , Doxorrubicina/farmacología , Doxorrubicina/administración & dosificación , Dióxido de Silicio/química , Animales , Resistencia a Antineoplásicos/efectos de los fármacos , Humanos , Nanopartículas/química , Línea Celular Tumoral , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/farmacología , Porosidad , Ratones , Apoptosis/efectos de los fármacos , Ratones Endogámicos BALB C , Ácidos Nucleicos/administración & dosificación , Polietileneimina/química , Ensayos Antitumor por Modelo de Xenoinjerto , Portadores de Fármacos/química , Proliferación Celular/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/administración & dosificaciónRESUMEN
Lipid-based vectors are becoming promising alternatives to traditional therapies over the last 2 decades specially for managing life-threatening diseases like cancer. Cationic lipids are the most prevalent non-viral vectors utilized in gene delivery. The increasing number of clinical trials about lipoplex-based gene therapy demonstrates their potential as well-established technology that can provide robust gene transfection. In this regard, this review will summarize this important point. These vectors however have a modest transfection efficiency. This limitation can be partly addressed by using functional lipids that provide a plethora of options for investigating nucleic acid-lipid interactions as well as in vitro and in vivo nucleic acid delivery for biomedical applications. Despite their lower gene transfer efficiency, lipid-based vectors such as lipoplexes have several advantages over viral ones: they are less toxic and immunogenic, can be targeted, and are simple to produce on a large scale. Researchers are actively investigating the parameters that are essential for an effective lipoplex delivery method. These include factors that influence the structure, stability, internalization, and transfection of the lipoplex. Thorough understanding of the design principles will enable synthesis of customized lipoplex formulations for life-saving therapy.
Asunto(s)
Técnicas de Transferencia de Gen , Terapia Genética , Lípidos , Liposomas , Humanos , Lípidos/química , Terapia Genética/métodos , Liposomas/química , Animales , Transfección/métodos , Vectores Genéticos/química , Ácidos Nucleicos/química , Ácidos Nucleicos/administración & dosificaciónRESUMEN
Nucleic acid-based therapies are transforming medicine, but rely on an efficient delivery vehicle such as lipid nanoparticles (LNPs). Concerns exists in the nanomedicine field, that a large fraction of the LNPs in the ensemble does not contain any nucleic acid cargo and thus exert no functional effect. Nevertheless, how LNP lipid formulation, the LNP preparation method employed and nucleic acid cargo size correlates with the proportion of empty LNPs remains largely unexplored. Here we employ a well-established single particle based method to study nucleic acid loading heterogeneity in LNPs. We find that only a minor fraction of LNPs are "empty", both for LNPs loaded with siRNA, mRNA and plasmids. For clinically relevant LNPs for mRNA delivery, we never detected more than 16% empty nanoparticles in the ensemble. Thus employing standard LNP lipid-cargo combinations and preparation schemes results in LNPs with the potential to serve their biomedical function.
Asunto(s)
Lípidos , Nanopartículas , ARN Interferente Pequeño , Nanopartículas/química , Lípidos/química , ARN Interferente Pequeño/química , ARN Interferente Pequeño/administración & dosificación , Tamaño de la Partícula , ARN Mensajero/genética , Plásmidos/química , Humanos , Ácidos Nucleicos/química , Ácidos Nucleicos/administración & dosificación , Propiedades de Superficie , LiposomasRESUMEN
Nucleic acid drugs show immense therapeutic potential, but achieving selective organ targeting (SORT) for pulmonary disease therapy remains a formidable challenge due to the high mortality rate caused by pulmonary embolism via intravenous administration or the mucus barrier in the respiratory tract via nebulized delivery. To meet this important challenge, we propose a new strategy to prepare lung-selective nucleic-acid vectors generated by in vivo decoration of lung-targeting proteins on bioreducible polyplexes. First, we synthesized polyamidoamines, named pabol and polylipo, to encapsulate and protect nucleic acids, forming polyamidoamines/mRNA polyplexes. Second, bovine serum albumin (BSA) was coated on the surface of these polyplexes, called BSA@polyplexes, including BSA@pabol polyplexes and BSA@polylipo polyplexes, to neutralize excess positive charge, thereby enhancing biosafety. Finally, after subcutaneous injection, proteins, especially vitronectin and fibronectins, attached to the polyplexes, resulting in the formation of lung-selective nucleic-acid vectors that achieve efficient lung targeting.
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Pulmón , Albúmina Sérica Bovina , Animales , Pulmón/metabolismo , Albúmina Sérica Bovina/química , Albúmina Sérica Bovina/administración & dosificación , Ratones , Bovinos , Humanos , Poliaminas/química , Ácidos Nucleicos/química , Ácidos Nucleicos/administración & dosificación , ARN Mensajero/administración & dosificaciónRESUMEN
CRISPR/Cas technology presents a promising approach for treating a wide range of diseases, including cancer and genetic disorders. Despite its potential, the translation of CRISPR/Cas into effective in-vivo gene therapy encounters challenges, primarily due to the need for safe and efficient delivery mechanisms. Lipid nanoparticles (LNPs), FDA-approved for RNA delivery, show potential for delivering also CRISPR/Cas, offering the capability to efficiently encapsulate large mRNA molecules with single guide RNAs. However, achieving precise targeting in-vivo remains a significant obstacle, necessitating further research into optimizing LNP formulations. Strategies to enhance specificity, such as modifying LNP structures and incorporating targeting ligands, are explored to improve organ and cell type targeting. Furthermore, the development of base and prime editing technology presents a potential breakthrough, offering precise modifications without generating double-strand breaks (DSBs). Prime editing, particularly when delivered via targeted LNPs, holds promise for treating diverse diseases safely and precisely. This review assesses both the progress made and the persistent challenges faced in using LNP-encapsulated CRISPR-based technologies for therapeutic purposes, with a particular focus on clinical translation.
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Sistemas CRISPR-Cas , Edición Génica , Lípidos , Nanopartículas , Humanos , Edición Génica/métodos , Nanopartículas/química , Lípidos/química , Animales , Terapia Genética/métodos , Técnicas de Transferencia de Gen , Ácidos Nucleicos/administración & dosificación , LiposomasRESUMEN
BACKGROUND & AIMS: The spread of foot-and-mouth disease virus (FMDV) through aerosol droplets among cloven-hoofed ungulates in close contact is a major obstacle for successful animal husbandry. Therefore, the development of suitable mucosal vaccines, especially nasal vaccines, to block the virus at the initial site of infection is crucial. PATIENTS AND METHODS: Here, we constructed eukaryotic expression plasmids containing the T and B-cell epitopes (pTB) of FMDV in tandem with the molecular mucosal adjuvant Fms-like tyrosine kinase receptor 3 ligand (Flt3 ligand, FL) (pTB-FL). Then, the constructed plasmid was electrostatically attached to mannose-modified chitosan-coated poly(lactic-co-glycolic) acid (PLGA) nanospheres (MCS-PLGA-NPs) to obtain an active nasal vaccine targeting the mannose-receptor on the surface of antigen-presenting cells (APCs). RESULTS: The MCS-PLGA-NPs loaded with pTB-FL not only induced a local mucosal immune response, but also induced a systemic immune response in mice. More importantly, the nasal vaccine afforded an 80% protection rate against a highly virulent FMDV strain (AF72) when it was subcutaneously injected into the soles of the feet of guinea pigs. CONCLUSIONS: The nasal vaccine prepared in this study can effectively induce a cross-protective immune response against the challenge with FMDV of same serotype in animals and is promising as a potential FMDV vaccine.
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Administración Intranasal , Quitosano , Virus de la Fiebre Aftosa , Fiebre Aftosa , Nanosferas , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Vacunas Virales , Animales , Quitosano/química , Quitosano/administración & dosificación , Virus de la Fiebre Aftosa/inmunología , Virus de la Fiebre Aftosa/genética , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Fiebre Aftosa/prevención & control , Fiebre Aftosa/inmunología , Ratones , Nanosferas/química , Vacunas Virales/inmunología , Vacunas Virales/administración & dosificación , Ratones Endogámicos BALB C , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Femenino , Ácidos Nucleicos/administración & dosificación , Inmunidad Mucosa , Sistemas de Liberación de MedicamentosRESUMEN
Rationale: Nucleic acid constructs are commonly used for vaccination, immune stimulation, and gene therapy, but their use in cancer still remains limited. One of the reasons is that systemic delivery to tumor-associated antigen-presenting cells (dendritic cells and macrophages) is often inefficient, while off-target nucleic acid-sensing immune pathways can stimulate systemic immune responses. Conversely, certain carbohydrate nanoparticles with small molecule payloads have been shown to target these cells efficiently in the tumor microenvironment. Yet, nucleic acid incorporation into such carbohydrate-based nanoparticles has proven challenging. Methods: We developed a novel approach using cross-linked bis succinyl-cyclodextrin (b-s-CD) nanoparticles to efficiently deliver nucleic acids and small-molecule immune enhancer to phagocytic cells in tumor environments and lymph nodes. Our study involved incorporating these components into the nanoparticles and assessing their efficacy in activating antigen-presenting cells. Results: The multi-modality immune stimulators effectively activated antigen-presenting cells and promoted anti-tumor immunity in vivo. This was evidenced by enhanced delivery to phagocytic cells and subsequent immune response activation in tumor environments and lymph nodes. Conclusion: Here, we describe a new approach to incorporating both nucleic acids and small-molecule immune enhancers into cross-linked bis succinyl-cyclodextrin (b-s-CD) nanoparticles for efficient delivery to phagocytic cells in tumor environments and lymph nodes in vivo. These multi-modality immune stimulators can activate antigen-presenting cells and foster anti-tumor immunity. We argue that this strategy can potentially be used to enhance anti-tumor efficacy.
Asunto(s)
Células Dendríticas , Nanopartículas , Ácidos Nucleicos , Células Dendríticas/inmunología , Células Dendríticas/efectos de los fármacos , Animales , Ácidos Nucleicos/administración & dosificación , Ratones , Nanopartículas/química , Ciclodextrinas/química , Ratones Endogámicos C57BL , Humanos , Línea Celular Tumoral , Tropismo , Microambiente Tumoral/efectos de los fármacos , Ganglios Linfáticos/inmunología , Femenino , Neoplasias/terapia , Neoplasias/inmunologíaRESUMEN
The FDA has approved many nucleic acid (NA)-based products. The presence of charges and biological barriers however affect stability and restrict widespread use. The electrostatic complexation of peptide with polyethylene glycol-nucleic acids (PEG-NAs) via nonreducible and reducible agents lead to three parts at one platform.. The reducible linkage made detachment of siRNA from PEG easy compared with a nonreducible linkage. A peptide spider produces a small hydrodynamic particle size, which can improve drug release and pharmacokinetics. Several examples of peptide spiders that enhance stability, protection and transfection efficiency are discussed. Moreover, this review also covers the challenges, future perspectives and unmet needs of peptide-PEG-NAs conjugates for NAs delivery.
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Ácidos Nucleicos , Péptidos , Humanos , Péptidos/química , Péptidos/administración & dosificación , Ácidos Nucleicos/administración & dosificación , Animales , Polietilenglicoles/química , Sistemas de Liberación de Medicamentos , Arañas , ARN Interferente Pequeño/administración & dosificaciónRESUMEN
Nanomaterials possess unusual physicochemical properties including unique optical, magnetic, electronic properties, and large surface-to-volume ratio. However, nanomaterials face some challenges when they were applied in the field of biomedicine. For example, some nanomaterials suffer from the limitations such as poor selectivity and biocompatibility, low stability, and solubility. To address the above-mentioned obstacles, functional nucleic acid has been widely served as a powerful and versatile ligand for modifying nanomaterials because of their unique characteristics, such as ease of modification, excellent biocompatibility, high stability, predictable intermolecular interaction and recognition ability. The functionally integrating functional nucleic acid with nanomaterials has produced various kinds of nanocomposites and recent advances in applications of functional nucleic acid decorated nanomaterials for cancer imaging and therapy were summarized in this review. Further, we offer an insight into the future challenges and perspectives of functional nucleic acid decorated nanomaterials.
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Nanoestructuras , Neoplasias , Ácidos Nucleicos , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/diagnóstico por imagen , Nanoestructuras/química , Ácidos Nucleicos/administración & dosificación , Ácidos Nucleicos/química , AnimalesRESUMEN
INTRODUCTION: Nucleic acid-based therapeutics offer groundbreaking potential for treating genetic diseases and advancing next-generation vaccines. Despite their promise, challenges in efficient delivery persist due to the properties of nucleic acids. Nanoparticles (NPs) serve as vital carriers, facilitating effective delivery to target cells, and addressing these challenges. Understanding the global landscape of patents in this field is essential for fostering innovation and guiding decision-making for researchers, the pharmaceutical industry, and regulatory agencies. AREAS COVERED: This review provides a comprehensive overview of patent compositions, applications, and manufacturing aspects concerning NPs as nucleic acid delivery systems. It delves into temporal trends, protection locations, market dynamics, and the most influential technological domains. In this work, we provide valuable insights into the advancements and potential of NP-based nucleic acid delivery systems, with a special focus on their pivotal role in advancing cutting-edge therapeutic solutions. EXPERT OPINION: Investment in NPs for nucleic acid delivery has significantly surged in recent years. However, translating these therapies into clinical practice faces obstacles, including the need for robust clinical evidence, regulatory compliance, and streamlined manufacturing processes. To address these challenges, our review article summarizes recent advances. We aim to engage researchers worldwide in the development of these promising technologies.
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Sistemas de Liberación de Medicamentos , Nanopartículas , Ácidos Nucleicos , Patentes como Asunto , Humanos , Ácidos Nucleicos/administración & dosificación , Animales , Portadores de Fármacos/química , Terapia Genética/métodosRESUMEN
The advent of lipid nanoparticles (LNPs) containing ionizable cationic lipids has enabled the encapsulation, stabilization, and intracellular delivery of nucleic acid payloads, leading to FDA-approved siRNA-based therapy and mRNA-based vaccines. Other nucleic acid-based therapeutic modalities, including protein replacement and CRISPR-mediated gene knockout and editing, are being tested in clinical trials, in many cases, for the treatment of liver-related diseases. However, to fully exploit these therapies beyond the liver, improvements in their delivery to extrahepatic targets are needed. Towards this end, both active targeting strategies based on targeting ligands grafted onto LNPs and passive targeting relying on physicochemical LNP parameters such as surface composition, charge, and size are being evaluated. Often, the latter strategy depends on the interaction of LNPs with blood components, forming what is known as the biomolecular corona. Here, I discuss potential challenges related to current LNP-based targeting strategies and the studies of the biomolecular corona on LNPs. I propose potential solutions to overcome some of these obstacles and present approaches currently being tested in preclinical and clinical studies, which face fewer biological barriers than traditional organ-targeting approaches.
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Lípidos , Nanopartículas , Ácidos Nucleicos , Humanos , Nanopartículas/química , Animales , Lípidos/química , Ácidos Nucleicos/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , ARN Interferente Pequeño/administración & dosificación , Terapia Genética/métodos , LiposomasRESUMEN
Oral squamous cell carcinoma (OSCC), a type of malignant tumour that primarily occurs in the oral mucosa, has drawn considerable attention owing to its aggressive growth and potentially high metastatic rate. Surgical resection is the primary treatment method for OSCC and is typically combined with radiation therapy and chemotherapy. microRNA-149-3p (miR-149) is a negative regulator of the Pi3k/Akt pathway and can effectively inhibit the proliferation of tumour cells. However, the application of miR-149 is limited owing to its relatively low efficiency of cellular uptake and poor stability when used alone. To overcome these challenges, this study adopted a novel nucleic acid nanostructured material, tetrahedral framework nucleic acids (tFNAs). The use of tFNAs as carriers to assemble the T-miR-149 complex reduced the expression of Pi3k and Akt involved in tumorigenesis and alterations in proteins related to cell apoptosis. The results indicated that the bionic drug delivery system has an effective tumour suppressive effect on OSCC in mice, revealing its potential clinical value in the treatment of OSCC.
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Carcinoma de Células Escamosas , MicroARNs , Neoplasias de la Boca , Proteínas Proto-Oncogénicas c-akt , MicroARNs/genética , MicroARNs/administración & dosificación , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/patología , Neoplasias de la Boca/metabolismo , Animales , Humanos , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/metabolismo , Ratones , Línea Celular Tumoral , Proteínas Proto-Oncogénicas c-akt/metabolismo , Apoptosis/efectos de los fármacos , Ratones Desnudos , Fosfatidilinositol 3-Quinasas/metabolismo , Proliferación Celular/efectos de los fármacos , Ratones Endogámicos BALB C , Ácidos Nucleicos/uso terapéutico , Ácidos Nucleicos/administración & dosificación , Sistemas de Liberación de Medicamentos/métodosRESUMEN
Pulmonary delivery of therapeutic agents has been considered the desirable administration route for local lung disease treatment. As the latest generation of therapeutic agents, nucleic acid has been gradually developed as gene therapy for local diseases such as asthma, chronic obstructive pulmonary diseases, and lung fibrosis. The features of nucleic acid, specific physiological structure, and pathophysiological barriers of the respiratory tract have strongly affected the delivery efficiency and pulmonary bioavailability of nucleic acid, directly related to the treatment outcomes. The development of pharmaceutics and material science provides the potential for highly effective pulmonary medicine delivery. In this review, the key factors and barriers are first introduced that affect the pulmonary delivery and bioavailability of nucleic acids. The advanced inhaled materials for nucleic acid delivery are further summarized. The recent progress of platform designs for improving the pulmonary delivery efficiency of nucleic acids and their therapeutic outcomes have been systematically analyzed, with the application and the perspectives of advanced vectors for pulmonary gene delivery.