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Natural killer (NK) cell-based immunotherapy has received much attention in recent years. However, the practical application is still suffering from the decreased function, inadequate infiltration, and immunosuppressive microenvironment in solid tumor. Herein, we construct the light-responsive porphyrin Fe array-armed NK cells (denoted as NK@p-Fe) for cell behavior modulation via bioorthogonal catalysis. By installing cholesterol-modified porphyrin Fe molecules on NK cell surface, it forms a catalytic array with light-harvesting capabilities. This functionality transforms NK cells into cellular factories, capable of catalyzing the production of active agents in a light-controlled manner. The NK@p-Fe can generate active antineoplastic drug doxorubicin through bioorthogonal reactions to enhance the cytotoxic function of NK cells. Beyond drug synthesis, the NK@p-Fe can also bioorthogonally catalyze to produce FDA approved immune agonist, imiquimod (IMQ). The activated immune agonist plays a dual role by inducing DC maturation for NK cells activation and reshaping tumor immunosuppressive microenvironment for NK cells infiltration. This work represents a paradigm for modulation of adoptive cell behaviors to boost cancer immunotherapy by bioorthogonal catalysis.
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Rectifying the aberrant microenvironment of a disease through maintenance of redox homeostasis has emerged as a promising perspective with significant therapeutic potential for Alzheimer's disease (AD). Herein, we design and construct a novel nanozyme-boosted MOF-CRISPR platform (CMOPKP), which can maintain redox homeostasis and rescue the impaired microenvironment of AD. By modifying the targeted peptides KLVFFAED, CMOPKP can traverse the blood-brain barrier and deliver the CRISPR activation system for precise activation of the Nrf2 signaling pathway and downstream redox proteins in regions characterized by oxidative stress, thereby reinstating neuronal antioxidant capacity and preserving redox homeostasis. Furthermore, cerium dioxide possessing catalase enzyme-like activity can synergistically alleviate oxidative stress. Further in vivo studies demonstrate that CMOPKP can effectively alleviate cognitive impairment in 3xTg-AD mouse models. Therefore, our design presents an effective way for regulating redox homeostasis in AD, which shows promise as a therapeutic strategy for mitigating oxidative stress in AD.
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Enfermedad de Alzheimer , Estrés Oxidativo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/genética , Animales , Ratones , Estrés Oxidativo/efectos de los fármacos , Humanos , Factor 2 Relacionado con NF-E2/metabolismo , Estructuras Metalorgánicas/química , Modelos Animales de Enfermedad , Sistemas CRISPR-Cas/genética , Cerio/química , Cerio/uso terapéutico , Cerio/farmacología , Barrera Hematoencefálica/metabolismo , Oxidación-Reducción , Antioxidantes/química , Antioxidantes/farmacología , Antioxidantes/uso terapéuticoRESUMEN
Bioorthogonal chemistry has provided an elaborate arsenal to manipulate native biological processes in living systems. As the great advancement of nanotechnology in recent years, bioorthogonal nanozymes are innovated to tackle the challenges that emerged in practical biomedical applications. Bioorthogonal nanozymes are uniquely positioned owing to their advantages of high customizability and tunability, as well as good adaptability to biological systems, which bring exciting opportunities for biomedical applications. More intriguingly, the great advancement in nanotechnology offers an exciting opportunity for innovating bioorthogonal catalytic materials. In this comprehensive review, the significant progresses of bioorthogonal nanozymes are discussed with both spatiotemporal controllability and high performance in living systems, and highlight their design principles and recent rapid applications. The remaining challenges and future perspectives are then outlined along this thriving field. It is expected that this review will inspire and promote the design of novel bioorthogonal nanozymes, and facilitate their clinical translation.
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N6-Methyladenosine (m6A) methylation plays a critical role in controlling the RNA fate. Emerging evidence has demonstrated that aberrant m6A methylation in immune cells such as macrophages could alter cell homeostasis and function, which can be a promising target for disease treatment. Despite tremendous progress in regulating the level of m6A methylation, the current methods suffer from the time-consuming operation and annoying off-target effect, which hampers the in situ manipulation of m6A methylation. Here, a bioorthogonal in situ modulation strategy of m6A methylation was proposed. Well-designed covalent organic framework (COF) dots (CIDM) could deprotect the agonist prodrug of m6A methyltransferase, resulting in a considerable hypermethylation of m6A modification. Simultaneously, the bioorthogonal catalyst CIDM showed oxidase (OXD)-mimic activity that further promoted the level of m6A methylation. Ultimately, the potential therapeutic effect of bioorthogonal controllable regulation of m6A methylation was demonstrated through intracellular bacteria eradication. The remarkable antimicrobial outcomes indicate that upregulating m6A methylation in macrophages could reprogram them into the M1 phenotype with high bactericidal activity. We believe that our bioorthogonal chemistry-controlled epigenetics regulatory strategy will provide a unique insight into the development of controllable m6A methylation.
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Current phototherapeutic approaches for Alzheimer's disease (AD) exhibit restricted clinical outcomes due to the limited physical penetration and comprised brain microenvironment of noninvasive nanomedicine. Herein, a hydrogen-bonded organic framework (HOF) based sonosensitizer is designed and synthesized. Mn-TCPP, a planar molecule where Mn2+ ion is chelated in the core with a large p-conjugated system and 4 carboxylate acid groups, has been successfully used as building blocks to construct an ultrasound-sensitive HOF (USI-MHOF), which can go deep in the brain of AD animal models. The both in vitro and in vivo studies indicate that USI-MHOF can generate singlet oxygen (1O2) and oxidize ß-amyloid (Aß) to inhibit aggregation, consequently attenuating Aß neurotoxicity. More intriguingly, USI-MHOF exhibits catalase (CAT)- and superoxide dismutase (SOD)-like activities, mitigating neuron oxidative stress and reprograming the brain microenvironment. For better crossing the blood-brain barrier (BBB), the peptide KLVFFAED (KD8) has been covalently grafted to USI-MHOF for improving BBB permeability and Aß selectivity. Further, in vivo experiments demonstrate a significant reduction of the craniocerebral Aß plaques and improvement of the cognition deficits in triple-transgenic AD (3×Tg-AD) mice models following deep-penetration ultrasound treatment. The work provides the first example of an ultrasound-responsive biocompatible HOF as non-invasive nanomedicine for in-depth treatment of AD.
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Despite the demonstrated importance of DNA G-quadruplexes (G4s) in health and disease, technologies to readily manipulate specific G4 folding for functional analysis and therapeutic purposes are lacking. Here we employ G4-stabilizing protein/ligand in conjunction with CRISPR to selectively facilitate single or multiple targeted G4 folding within specific genomic loci. We demonstrate that fusion of nucleolin with a catalytically inactive Cas9 can specifically stabilize G4s in the promoter of oncogene MYC and muscle-associated gene Itga7 as well as telomere G4s, leading to cell proliferation arrest, inhibition of myoblast differentiation and cell senescence, respectively. Furthermore, CRISPR can confer intra-G4 selectivity to G4-binding compounds pyridodicarboxamide and pyridostatin. Compared with traditional G4 ligands, CRISPR-guided biotin-conjugated pyridodicarboxamide enables a more precise investigation into the biological functionality of de novo G4s. Our study provides insights that will enhance understanding of G4 functions and therapeutic interventions.
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Sistemas CRISPR-Cas , G-Cuádruplex , Nucleolina , Proteínas de Unión al ARN , Humanos , Ligandos , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Fosfoproteínas/metabolismo , Fosfoproteínas/genética , Ácidos Picolínicos/farmacología , Ácidos Picolínicos/química , Proliferación Celular/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Animales , Senescencia Celular/efectos de los fármacos , Senescencia Celular/genética , Proteína 9 Asociada a CRISPR/metabolismo , Proteína 9 Asociada a CRISPR/genética , Regiones Promotoras Genéticas , Telómero/metabolismo , Telómero/genética , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Piridinas/farmacología , Piridinas/química , ADN/metabolismo , ADN/genética , Ratones , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Células HEK293 , Mioblastos/metabolismo , Mioblastos/citología , AminoquinolinasRESUMEN
Alzheimer's disease (AD) is a devastating neurodegenerative disease that affects â¼50 million people globally. The accumulation of amyloid-ß (Aß) plaques, a predominant pathological feature of AD, plays a crucial role in AD pathogenesis. In this respect, Aß has been regarded as a highly promising therapeutic target for AD treatment. Polyoxometalates (POMs) are a novel class of metallodrugs being developed as modulators of Aß aggregation, owing to their negative charge, polarity, and three-dimensional structure. Unlike traditional discrete inorganic complexes, POMs contain tens to hundreds of metal atoms, showcasing remarkable tunability and diversity in nuclearities, sizes, and shapes. The easily adjustable and structurally variable nature of POMs allows for their favorable interactions with Aß. This mini-review presents a balanced overview of recent progress in using POMs to mitigate amyloidosis. Clear correlations between anti-amyloid activities and structural features of POMs are also elaborated in detail. Finally, we discuss the current challenges and future prospects of POMs in combating AD.
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Bioorthogonal chemistry represents a powerful tool in chemical biology, which shows great potential in epigenetic modulation. As a proof of concept, the epigenetic modulation model of mitochondrial DNA (mtDNA) is selected because mtDNA establishes a relative hypermethylation stage under oxidative stress, which impairs the mitochondrion-based therapeutic effect during cancer therapy. Herein, we design a new biocompatible hydrogen-bonded organic framework (HOF) for a HOF-based mitochondrion-targeting bioorthogonal platform TPP@P@PHOF-2. PHOF-2 can activate a prodrug (pro-procainamide) in situ, which can specifically inhibit DNA methyltransferase 1 (DNMT1) activity and remodel the epigenetic modification of mtDNA, making it more susceptible to ROS damage. In addition, PHOF-2 can also catalyze artemisinin to produce large amounts of ROS, effectively damaging mtDNA and achieving better chemodynamic therapy demonstrated by both in vitro and in vivo studies. This work provides new insights into developing advanced bioorthogonal therapy and expands the applications of HOF and bioorthogonal catalysis.
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ADN Mitocondrial , Epigénesis Genética , Mitocondrias , Especies Reactivas de Oxígeno , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Humanos , ADN Mitocondrial/genética , Epigénesis Genética/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Enlace de Hidrógeno , Animales , Ratones , ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , ADN (Citosina-5-)-Metiltransferasa 1/antagonistas & inhibidores , ADN (Citosina-5-)-Metiltransferasa 1/genética , Profármacos/farmacología , Profármacos/química , Estructuras Metalorgánicas/química , Estructuras Metalorgánicas/farmacologíaRESUMEN
Pyroptosis has garnered increasing attention because of its ability to trigger robust antitumor immunity. Pyroptosis is initiated by the activation of inflammasomes, which are regulated by various organelles. The collaboration among organelles offers several protective mechanisms to prevent activation of the inflammasome, thereby limiting the induction of efficient pyroptosis. Herein, a multiorganelle homeostasis disruptor (denoted BLL) is constructed by encapsulating liposomes and bortezomib (BTZ) within a layered double hydroxide (LDH) nanocage to continuously activate inflammasomes for inducing efficient pyroptosis. In lysosomes, the negatively charged liposomes are released to recruit the NLRP3 inflammasomes through electrostatic interactions. ER stress is induced by BTZ to enhance the activation of the NLRP3 inflammasome. Meanwhile, the BLL nanocage exhibited H+-scavenging ability due to the weak alkalinity of LDH, thus disrupting the homeostasis of the lysosome and alleviating the degradation of the NLRP3 inflammasome by lysosomal-associated autophagy. Our results suggest that the BLL nanocage induces homeostatic imbalance in various organelles and efficient pyroptosis. We hope this work can provide new insights into the design of an efficient pyroptosis inducer by disrupting the homeostatic balance of multiple organelles and promote the development of novel antineoplastic platforms.
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Homeostasis , Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Piroptosis , Piroptosis/efectos de los fármacos , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacos , Homeostasis/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Humanos , Ratones , Bortezomib/farmacología , Bortezomib/química , Liposomas/química , Animales , Lisosomas/metabolismo , Lisosomas/efectos de los fármacos , Hidróxidos/química , Hidróxidos/farmacología , Nanoestructuras/química , Nanopartículas/químicaRESUMEN
Bioorthogonal chemistry has emerged as a powerful tool for manipulating biological processes. However, difficulties in controlling the exact location and on-demand catalytic synthesis limit its application in biological systems. Herein, this work constructs an activatable bioorthogonal system integrating a shielded catalyst and prodrug molecules to combat biofilm-associated infections. The catalytic species is activated in response to the hyaluronidase (HAase) secreted by the bacteria and the acidic pH of the biofilm, which is accompanied by the release of prodrugs, to achieve the bioorthogonal catalytic synthesis of antibacterial molecules in situ. Moreover, the system can produce reactive oxygen species (ROS) to disperse bacterial biofilms, enabling the antibacterial molecules to penetrate the biofilm and eliminate the bacteria within it. This study promotes the design of efficient and safe bioorthogonal catalysts and the development of bioorthogonal chemistry-mediated antibacterial strategies.
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Anticancer nanomedicines used for ferroptosis therapy generally rely on the direct delivery of Fenton catalysts to drive lipid peroxidation in cancer cells. However, the therapeutic efficacy is limited by the ferroptosis resistance caused by the intracellular anti-ferroptotic signals. Herein, we report the intrinsic ATPase-mimicking activity of a vanadium carbide MXene nanozyme (PVCMs) to pharmacologically modulate the nuclear factor erythroid 2-related factor 2 (Nrf2) program, which is the master anti-ferroptotic mediator in the ironclad defense system in triple-negative breast cancer (TNBC) cells. The PVCMs perform high ATPase-like activity that can effectively and selectively catalyze the dephosphorylation of ATP to generate ADP. Through a cascade mechanism initiated by falling energy status, PVCMs can powerfully hinder the Nrf2 program to selectively drive ferroptosis in TNBC cells in response to PVCMs-induced glutathione depletion. This study provides a paradigm for the use of pharmacologically active nanozymes to moderate specific cellular signals and elicit desirable pharmacological activities for therapeutic applications.
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Ferroptosis , Nitritos , Elementos de Transición , Neoplasias de la Mama Triple Negativas , Humanos , Adenosina Trifosfatasas , Factor 2 Relacionado con NF-E2 , Neoplasias de la Mama Triple Negativas/tratamiento farmacológicoRESUMEN
Bioorthogonal reactions provide a powerful tool to manipulate biological processes in their native environment. However, the transition-metal catalysts (TMCs) for bioorthogonal catalysis are limited to low atomic utilization and moderate catalytic efficiency, resulting in unsatisfactory performance in a complex physiological environment. Herein, sulfur-doped Fe single-atom catalysts with atomically dispersed and uniform active sites are fabricated to serve as potent bioorthogonal catalysts (denoted as Fe-SA), which provide a powerful tool for in situ manipulation of cellular biological processes. As a proof of concept, the N6-methyladensoine (m6A) methylation in macrophages is selectively regulated by the mannose-modified Fe-SA nanocatalysts (denoted as Fe-SA@Man NCs) for potent cancer immunotherapy. Particularly, the agonist prodrug of m6A writer METTL3/14 complex protein (pro-MPCH) can be activated in situ by tumor-associated macrophage (TAM)-targeting Fe-SA@Man, which can upregulate METTL3/14 complex protein expression and then reprogram TAMs for tumor killing by hypermethylation of m6A modification. Additionally, we find the NCs exhibit an oxidase (OXD)-like activity that further boosts the upregulation of m6A methylation and the polarization of macrophages via producing reactive oxygen species (ROS). Ultimately, the reprogrammed M1 macrophages can elicit immune responses and inhibit tumor proliferation. Our study not only sheds light on the design of single-atom catalysts for potent bioorthogonal catalysis but also provides new insights into the spatiotemporal modulation of m6A RNA methylation for the treatment of various diseases.
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Adenosina/análogos & derivados , Inmunoterapia , Neoplasias , Humanos , Metilación de ARN , Catálisis , MetiltransferasasRESUMEN
In situ drug synthesis using the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction has attracted considerable attention in tumor therapy because of its satisfactory effectiveness and reduced side-effects. However, the exogenous addition of copper catalysts can cause cytotoxicity and has hampered biomedical applications in vivo. Here, we design and synthesize a metal-organic framework (MOF) to mimic copper chaperone, which can selectively modulate copper trafficking for bioorthogonal synthesis with no need of exogenous addition of copper catalysts. Like copper chaperones, the prepared ZIF-8 copper chaperone mimics specifically bind copper ions through the formation of coordination bonds. Moreover, the copper is unloaded under the acidic environment due to the dissipation of the coordination interactions between metal ions and ligands. In this way, the cancer cell-targeted copper chaperone mimics can selectively transport copper ions into cells. Regulation of intracellular copper trafficking may inspire constructing bioorthogonal catalysis system with reduced metal cytotoxicity in live cells.
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Alquinos , Cobre , Cobre/farmacología , Cobre/química , Alquinos/química , Azidas/química , Reacción de Cicloadición , Catálisis , IonesRESUMEN
Nanozymes with intrinsic enzyme-mimicking activities have shown great potential to become surrogates of natural enzymes in many fields by virtue of their advantages of high catalytic stability, ease of functionalization, and low cost. However, due to the lack of predictable descriptors, most of the nanozymes reported in the past have been obtained mainly through trial-and-error strategies, and the catalytic efficacy, substrate specificity, as well as practical application effect under physiological conditions, are far inferior to that of natural enzymes. To optimize the catalytic efficacies and functions of nanozymes in biomedical settings, recent studies have introduced biosystem-inspired strategies into nanozyme design. In this review, recent advances in the engineering of biosystem-inspired nanozymes by leveraging the refined catalytic structure of natural enzymes, simulating the behavior changes of natural enzymes in the catalytic process, and mimicking the specific biological processes or living organisms, are introduced. Furthermore, the currently involved biomedical applications of biosystem-inspired nanozymes are summarized. More importantly, the current opportunities and challenges of the design and application of biosystem-inspired nanozymes are discussed. It is hoped that the studies of nanozymes based on bioinspired strategies will be beneficial for constructing the new generation of nanozymes and broadening their biomedical applications.
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Nanoestructuras , Nanoestructuras/química , Especificidad por Sustrato , CatálisisRESUMEN
Autophagosome-tethering compound (ATTEC) technology has recently been emerging as a novel approach for degrading proteins of interest (POIs). However, it still faces great challenges in how to design target-specific ATTEC molecules. Aptamers are single-stranded DNA or RNA oligonucleotides that can recognize their target proteins with high specificity and affinity. Here, ATTEC is combined with aptamers for POIs degradation. As a proof of concept, pathological protein α-synuclein (α-syn) is chosen as the target and an efficient α-syn degrader is generated. Aptamer as a targeting warhead of α-syn is conjugated with LC3B-binding compound 5,7-dihydroxy-4-phenylcoumarin (DP) via bioorthogonal click reaction. It is demonstrated that the aptamer conjugated with DP is capable of clearing α-syn through LC3 and autophagic degradation. These results indicate that aptamer-based ATTECs are a versatile approach to degrade POIs by taking advantage of the well-defined different aptamers for targeting diverse proteins, which provides a new way for the design of ATTECs to degradation of targeted proteins.
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Autofagosomas , alfa-Sinucleína , alfa-Sinucleína/metabolismo , Autofagosomas/metabolismo , Autofagia , Lisosomas/metabolismo , Oligonucleótidos/metabolismoRESUMEN
Pyroptosis has garnered increasing attention in cancer immunotherapy. Moreover, increasing plasma membrane damage by reactive oxygen species (ROS) is considered an effective strategy for promoting pyroptosis. However, the current tactics for enhancing membrane rupture in pyroptosis are limited by the inherent drawbacks of ROS and the immunosuppressive tumor microenvironment. Herein, a self-adaptive pyroptosis inducer (LPZ) is designed by integrating Lactobacillus rhamnosus GG (LGG) and an enzyme-like metal-organic framework to achieve potent pyroptosis immunotherapy. LPZ can adhere to cancer cell membranes through the interaction between the pili of LGG and the mucin of cancer cells. In particular, the adaptive formula can gradually enhance the ability of nanozymes to produce ROS by creating an acidic microenvironment through anaerobic respiration. These results verify that LPZ could generate high levels of ROS both on the membrane and within cancer cells, leading to pyroptotic cell death and strong antitumor immunity. Meanwhile, LGG are eventually killed by ROS in this process to halt their respiration and prevent potential biosafety concerns. Overall, this work provides new inspiration for the design of self-adaptive nanocatalytic drugs for cancer immunotherapy.
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Neoplasias , Piroptosis , Humanos , Especies Reactivas de Oxígeno , Membrana Celular , Catálisis , Inmunoterapia , Microambiente Tumoral , Neoplasias/terapiaRESUMEN
Immunotherapy of triple-negative breast cancer (TNBC) has an unsatisfactory therapeutic outcome due to an immunologically "cold" microenvironment. Fusobacterium nucleatum (F. nucleatum) was found to be colonized in triple-negative breast tumors and was responsible for the immunosuppressive tumor microenvironment and tumor metastasis. Herein, we constructed a bacteria-derived outer membrane vesicle (OMV)-coated nanoplatform that precisely targeted tumor tissues for dual killing of F. nucleatum and cancer cells, thus transforming intratumor bacteria into immunopotentiators in immunotherapy of TNBC. The as-prepared nanoparticles efficiently induced immunogenic cell death through a Fenton-like reaction, resulting in enhanced immunogenicity. Meanwhile, intratumoral F. nucleatum was killed by metronidazole, resulting in the release of pathogen-associated molecular patterns (PAMPs). PAMPs cooperated with OMVs further facilitated the maturation of dendritic cells and subsequent T-cell infiltration. As a result, the "kill two birds with one stone" strategy warmed up the cold tumor environment, maximized the antitumor immune response, and achieved efficient therapy of TNBC as well as metastasis prevention. Overall, this strategy based on a microecology distinction in tumor and normal tissue as well as microbiome-induced reversal of cold tumors provides new insight into the precise and efficient immune therapy of TNBC.
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Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/metabolismo , Adyuvantes Inmunológicos , Moléculas de Patrón Molecular Asociado a Patógenos/metabolismo , Moléculas de Patrón Molecular Asociado a Patógenos/uso terapéutico , Inmunoterapia/métodos , Fusobacterium nucleatum/metabolismo , Línea Celular Tumoral , Microambiente TumoralRESUMEN
The infectious disease coronavirus 2019 (SARS-CoV-2) is caused by a virus that has RNA as its genetic material. To understand the detailed structural features of SARS-COV-2 RNA, we probed the RNA structure by NMR. Two RNA sequences form a duplex and self-associate to form a dimeric G-quadruplex. The FrG nucleoside was employed as a 19F sensor to confirm the RNA structure in cells by 19F NMR. A FRET assay further demonstrated that the dimeric G-quadruplex resulted in RNA dimerization in cells. These results provide the basis for the elucidation of SARS-COV-2 RNA function, which provides new insights into developing novel antiviral drugs against SARS-COV-2.
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COVID-19 , G-Cuádruplex , Humanos , SARS-CoV-2 , ARN Viral/genética , DimerizaciónRESUMEN
Hydrogen-bonded organic frameworks (HOFs) are an emerging attractive class of highly crystalline porous materials characterized by significant biocompatibility, rich chemical functionalities and well-defined porosity. The unique advantages including metal-free nature and reversible binding manner significantly distinguish HOFs from other porous materials in the biotechnology and biomedical field. However, the relevant HOF studies still remain in their infancy despite the promising and remarkable results that have been presented in recent years. Due to the intricate and dynamic nature of physiological conditions, the major challenge lies in the stability and structural diversity of HOFs in vivo. In this Tutorial Review, we summarize the common building blocks for the construction of HOF-based functional biomaterials and the latest developments in the biological field. Moreover, we highlight current challenges regarding the stability and functionalization of HOFs along with the corresponding potential solutions. This Tutorial Review will have a profound effect in future years on the design and applications of HOF-based biomaterials.
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Materiales Biocompatibles , Biotecnología , Hidrógeno , Porosidad , Relación Estructura-ActividadRESUMEN
The ability to regulate mitophagy in a living system with small molecules remains a great challenge. We hypothesize that adding fragments specific to the key autophagosome protein LC3 to mitochondria will mimic receptor-mediated mitophagy, thus engaging the autophagy-lysosome pathway to induce mitochondrial degradation. Herein, we develop a general biochemical approach to modulate mitophagy, dubbed mito-ATTECs, which employ chimera molecules composed of LC3-binding moieties linked to mitochondria-targeting ligands. Mito-ATTECs trigger mitophagy via targeting mitochondria to autophagosomes through direct interaction between mito-ATTECs and LC3 on mitochondrial membranes. Subsequently, autophagosomes containing mitochondria rapidly fuse with lysosomes to facilitate the degradation of mitochondria. Therefore, mito-ATTECs circumvent the detrimental effects related to disruption of mitochondrial membrane integrity by inducers routinely used to manipulate mitophagy, and provide a versatile biochemical approach to investigate the physiological roles of mitophagy. Furthermore, we found that sustained mitophagy lead to mitochondrial depletion and autophagic cell death in several malignant cell lines (lethal mitophagy). Among them, apoptosis-resistant malignant melanoma cell lines are particularly sensitive to lethal mitophagy. The therapeutic efficacy of mito-ATTECs has been further evaluated by using subcutaneous and pulmonary metastatic melanoma models. Together, the mitochondrial depletion achieved by mito-ATTECs may demonstrate the general concept of inducing cancer cell lethality through excessive mitochondrial clearance, establishing a promising therapeutic paradigm for apoptosis-resistant tumors.