Targeting capabilities of engineered extracellular vesicles for the treatment of neurological diseases

Recent advances in research on extracellular vesicles have significantly enhanced their potential as therapeutic agents for neurological diseases.Owing to their therapeutic properties and ability to cross the blood–brain barrier,extracellular vesicles are recognized as promising drug delivery vehicles for various neurological conditions,including ischemic stroke,traumatic brain injury,neurodegenerative diseases,glioma,and psychosis.However,the clinical application of natural extracellular vesicles is hindered by their limited targeting ability and short clearance from the body.To address these limitations,multiple engineering strategies have been developed to enhance the targeting capabilities of extracellular vesicles,thereby enabling the delivery of therapeutic contents to specific tissues or cells.Therefore,this review aims to highlight the latest advancements in natural and targeting-engineered extracellular vesicles,exploring their applications in treating traumatic brain injury,ischemic stroke,Parkinson's disease,Alzheimer's disease,amyotrophic lateral sclerosis,glioma,and psychosis.Additionally,we summarized recent clinical trials involving extracellular vesicles and discussed the challenges and future prospects of using targeting-engineered extracellular vesicles for drug delivery in treating neurological diseases.This review offers new insights for developing highly targeted therapies in this field.

Mitochondrial targeting sequence of magnetoreceptor MagR:More than just targeting

Iron-sulfur clusters(ISC)are essential cofactors for proteins involved in various biological processes,such as electron transport,biosynthetic reactions,DNA repair,and gene expression regulation.ISC assembly protein IscA1(or MagR)is found within the mitochondria of most eukaryotes.Magnetoreceptor(MagR)is a highly conserved A-type iron and iron-sulfur cluster-binding protein,characterized by two distinct types of iron-sulfur clusters,[2Fe-2S]and[3Fe-4S],each conferring unique magnetic properties.MagR forms a rod-like polymer structure in complex with photoreceptive cryptochrome(Cry)and serves as a putative magnetoreceptor for retrieving geomagnetic information in animal navigation.Although the N-terminal sequences of MagR vary among species,their specific function remains unknown.In the present study,we found that the N-terminal sequences of pigeon MagR,previously thought to serve as a mitochondrial targeting signal(MTS),were not cleaved following mitochondrial entry but instead modulated the efficiency with which iron-sulfur clusters and irons are bound.Moreover,the N-terminal region of MagR was required for the formation of a stable MagR/Cry complex.Thus,the N-terminal sequences in pigeon MagR fulfil more important functional roles than just mitochondrial targeting.These results further extend our understanding of the function of MagR and provide new insights into the origin of magnetoreception from an evolutionary perspective.

Precision targeting in hepatocellular carcinoma:Exploring ligandreceptor mediated nanotherapy

Hepatocellular carcinoma(HCC)is the most common primary liver cancer and poses a major challenge to global health due to its high morbidity and mortality.Conventional chemotherapy is usually targeted to patients with intermediate to advanced stages,but it is often ineffective and suffers from problems such as multidrug resistance,rapid drug clearance,nonspecific targeting,high side effects,and low drug accumulation in tumor cells.In response to these limitations,recent advances in nanoparticle-mediated targeted drug delivery technologies have emerged as breakthrough approaches for the treatment of HCC.This review focuses on recent advances in nanoparticle-based targeted drug delivery systems,with special attention to various receptors overexpressed on HCC cells.These receptors are key to enhancing the specificity and efficacy of nanoparticle delivery and represent a new paradigm for actively targeting and combating HCC.We comprehensively summarize the current understanding of these receptors,their role in nanoparticle targeting,and the impact of such targeted therapies on HCC.By gaining a deeper understanding of the receptor-mediated mechanisms of these innovative therapies,more effective and precise treatment of HCC can be achieved.

The functions of exosomes targeting astrocytes and astrocyte-derived exosomes targeting other cell types

Astrocytes are the most abundant glial cells in the central nervous system;they participate in crucial biological processes,maintain brain structure,and regulate nervous system function.Exosomes are cell-derived extracellular vesicles containing various bioactive molecules including proteins,peptides,nucleotides,and lipids secreted from their cellular sources.Increasing evidence shows that exosomes participate in a communication network in the nervous system,in which astrocyte-derived exosomes play important roles.In this review,we have summarized the effects of exosomes targeting astrocytes and the astrocyte-derived exosomes targeting other cell types in the central nervous system.We also discuss the potential research directions of the exosome-based communication network in the nervous system.The exosome-based intercellular communication focused on astrocytes is of great significance to the biological and/or pathological processes in different conditions in the brain.New strategies may be developed for the diagnosis and treatment of neurological disorders by focusing on astrocytes as the central cells and utilizing exosomes as communication mediators.

Multi-Scale Approach for Gold Targeting in Côte d’Ivoire Paleoproterozoic Rocks

The aim of this study is to contribute to better targeting of gold prospecting areas using geospatial information. To this end, 3 mining sites were selected for the study. They are: the Sénoufo belt (Barrick Gold mine), the Yaouré complex (Perseus Mining mine) and the South Fetêkro belt (Bonikro, Hiré and Agbaou mines). For this study, a multi-scale approach was carried out at regional, mine and microscopic levels. At the regional scale, a comparative analysis of 1:200,000 scale geological maps revealed that 3 main lithologies are regularly repeated on and around the various mining sites. These are: undifferentiated volcanics, metagranodiorites and metasiltites dominated by meta-arenites. Most of these lithologies are affected by undifferentiated faults generally oriented NE-SW, N-S, ENE-WSW and WNW-ESE. In addition, gold and manganese occurrences are present on all the sites studied. At the mine scale, radarsat-1 images processing indicate that the main mining sites are generally located near or at the intersection of lineaments-oriented NE-SW or N-S on the one hand and E-W or ENE-WSW or WNW-ESE or again NW-SE on the other. These mines are also located at the interface between zones of high and low lineament density. At the microscopic scale, petrographic studies of undifferentiated volcanic samples from the various sites indicate that they consist of andesites, meta-andesites and tuffs.

Targeting therapy for hepatocellular carcinoma by delivering microRNAs as exosomal cargo

Exosomes,the smallest extracellular vesicles,have gained significant attention as key mediators in intercellular communication,influencing both physiological and pathological processes,particularly in cancer progression.A recent review article by Wang et al was published in a timely manner to stimulate future research and facilitate practical developments for targeted treatment of hepatocellular carcinoma using exosomes,with a focus on the origin from which exosomes derive.If information about the mechanisms for delivering exosomes to specific cells is incorporated,the concept of targeted therapy for hepatocellular carcinoma using exosomes could be more comprehensively understood.

Enhanced Precision Therapy of Multiple Myeloma Through Engineered Biomimetic Nanoparticles with Dual Targeting

Multiple myeloma(MM)is the second most prevalent hematological malignancy.Current MM treatment strategies are hampered by systemic toxicity and suboptimal therapeutic efficacy.This study addressed these limitations through the development of a potent MM-targeting chemotherapy strategy,which capitalized on the high binding affinity of alendronate for hydroxyapatite in the bone matrix and the homologous targeting of myeloma cell membranes,termed T-PB@M.The results from our investigations highlight the considerable bone affinity of T-PB@M,both in vitro and in vivo.Additionally,this material demonstrated a capability for drug release triggered by low pH conditions.Moreover,T-PB@M induced the generation of reactive oxygen species and triggered cell apoptosis through the poly(ADP-ribose)polymerase 1(PARP1)-Caspase-3-B-cell lymphoma-2(Bcl-2)pathway in MM cells.Notably,T-PB@M preferentially targeted bone-involved sites,thereby circumventing systemic toxic side effects and leading to prolonged survival of MM orthotopic mice.Therefore,this designed target-MM nanocarrier presents a promising and potentially effective platform for the precise treatment of MM.

Targeting nuclear factor erythroid 2-related factor 2-regulated ferroptosis to treat nervous system diseases

By critically examining the work,we conducted a comprehensive bibliometric analysis on the role of nuclear factor erythroid 2-related factor 2(NRF2)in nervous system diseases.We also proposed suggestions for future bibliometric studies,including the integration of multiple websites,analytical tools,and analytical approaches,The findings presented provide compelling evidence that ferroptosis is closely associated with the therapeutic challenges of nervous system diseases.Targeted modulation of NRF2 to regulate ferroptosis holds substantial potential for effectively treating these diseases.Future NRF2-related research should not only focus on discovering new drugs but also on designing rational drug delivery systems.In particular,nanocarriers offer substantial potential for facilitating the clinical translation of NRF2 research and addressing existing issues related to NRF2-related drugs.

Degradation of FAK-targeting by proteolytic targeting chimera technology to inhibit the metastasis of hepatocellular carcinoma

Liver cancer is a prevalent malignant cancer,ranking third in terms of mortality rate.Metastasis and recurrence primarily contribute to the high mortality rate of liver cancer.Hepatocellular carcinoma(HCC)has low expression of focal adhesion kinase(FAK),which increases the risk of metastasis and recurrence.Nevertheless,the efficacy of FAK phosphorylation inhibitors is currently limited.Thus,investigating the mechanisms by which FAK affects HCC metastasis to develop targeted therapies for FAK may present a novel strategy to inhibit HCC metastasis.This study examined the correlation between FAK expression and the prognosis of HCC.Additionally,we explored the impact of FAK degradation on HCC metastasis through wound healing experiments,transwell invasion experiments,and a xenograft tumor model.The expression of proteins related to epithelial-mesenchymal transition(EMT)was measured to elucidate the underlying mechanisms.The results showed that FAK PROTAC can degrade FAK,inhibit the migration and invasion of HCC cells in vitro,and notably decrease the lung metastasis of HCC in vivo.Increased expression of E-cadherin and decreased expression of vimentin indicated that EMT was inhibited.Consequently,degradation of FAK through FAK PROTAC effectively suppressed liver cancer metastasis,holding significant clinical implications for treating liver cancer and developing innovative anti-neoplastic drugs.

Targeting neuronal PAS domain protein 2 and KN motif/ankyrin repeat domains 1:Advances in type 2 diabetes therapy

This editorial summarizes the latest literature on the roles of neuronal PAS domain protein 2 and KN motif/ankyrin repeat domain 1 in type 2 diabetes(T2D).We highlight their involvement inβ-cell dysfunction,explore their potential as therapeutic targets,and discuss the implications for new treatment strategies.We offer valuable insights into relevant gene regulation and cellular mechanisms relevant for the targeted management of T2D.

Multilevel analysis of the central-peripheral-target organ pathway:contributing to recovery after peripheral nerve injury

Peripheral nerve injury is a common neurological condition that often leads to severe functional limitations and disabilities.Research on the pathogenesis of peripheral nerve injury has focused on pathological changes at individual injury sites,neglecting multilevel pathological analysis of the overall nervous system and target organs.This has led to restrictions on current therapeutic approaches.In this paper,we first summarize the potential mechanisms of peripheral nerve injury from a holistic perspective,covering the central nervous system,peripheral nervous system,and target organs.After peripheral nerve injury,the cortical plasticity of the brain is altered due to damage to and regeneration of peripheral nerves;changes such as neuronal apoptosis and axonal demyelination occur in the spinal cord.The nerve will undergo axonal regeneration,activation of Schwann cells,inflammatory response,and vascular system regeneration at the injury site.Corresponding damage to target organs can occur,including skeletal muscle atrophy and sensory receptor disruption.We then provide a brief review of the research advances in therapeutic approaches to peripheral nerve injury.The main current treatments are conducted passively and include physical factor rehabilitation,pharmacological treatments,cell-based therapies,and physical exercise.However,most treatments only partially address the problem and cannot complete the systematic recovery of the entire central nervous system-peripheral nervous system-target organ pathway.Therefore,we should further explore multilevel treatment options that produce effective,long-lasting results,perhaps requiring a combination of passive(traditional)and active(novel)treatment methods to stimulate rehabilitation at the central-peripheral-target organ levels to achieve better functional recovery.

Pyroptosis,ferroptosis,and autophagy in spinal cord injury:regulatory mechanisms and therapeutic targets

Regulated cell death is a form of cell death that is actively controlled by biomolecules.Several studies have shown that regulated cell death plays a key role after spinal cord injury.Pyroptosis and ferroptosis are newly discovered types of regulated cell deaths that have been shown to exacerbate inflammation and lead to cell death in damaged spinal cords.Autophagy,a complex form of cell death that is interconnected with various regulated cell death mechanisms,has garnered significant attention in the study of spinal cord injury.This injury triggers not only cell death but also cellular survival responses.Multiple signaling pathways play pivotal roles in influencing the processes of both deterioration and repair in spinal cord injury by regulating pyroptosis,ferroptosis,and autophagy.Therefore,this review aims to comprehensively examine the mechanisms underlying regulated cell deaths,the signaling pathways that modulate these mechanisms,and the potential therapeutic targets for spinal cord injury.Our analysis suggests that targeting the common regulatory signaling pathways of different regulated cell deaths could be a promising strategy to promote cell survival and enhance the repair of spinal cord injury.Moreover,a holistic approach that incorporates multiple regulated cell deaths and their regulatory pathways presents a promising multi-target therapeutic strategy for the management of spinal cord injury.

Subretinal fibrosis secondary to neovascular age-related macular degeneration:mechanisms and potential therapeutic targets

Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central vision loss of patients with neovascular age-related macular degeneration.The pathogenesis of subretinal fibrosis is complex,and the underlying mechanisms are largely unknown.Therefore,there are no effective treatment options.A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments.The current article reviews several aspects of subretinal fibrosis,including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis;multimodal imaging techniques for subretinal fibrosis;animal models for studying subretinal fibrosis;cellular and non-cellular constituents of subretinal fibrosis;pathophysiological mechanisms involved in subretinal fibrosis,such as aging,infiltration of macrophages,different sources of mesenchymal transition to myofibroblast,and activation of complement system and immune cells;and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis,such as vascular endothelial growth factor,connective tissue growth factor,fibroblast growth factor 2,platelet-derived growth factor and platelet-derived growth factor receptor-β,transforming growth factor-βsignaling pathway,Wnt signaling pathway,and the axis of heat shock protein 70-Toll-like receptors 2/4-interleukin-10.This review will improve the understanding of the pathogenesis of subretinal fibrosis,allow the discovery of molecular targets,and explore potential treatments for the management of subretinal fibrosis.

Construction of Myostatin Gene Targeting Vector of Mouse

[Objective] This study aimed to construct Myostatin （MSTN） gene targeting vector of mouse. [Method] Total RNA was extracted from hindlimb muscle tissues of mouse to synthesize cDNA as the template to clone the coding region of MSTN. The CDS of MSTN gene including 3 kb 5’ homologous arm and 1.4 kb 3’ homologous arm were inserted into vector pBluescript_SK ＋ to construct the targeting vector pLoxP-5N3T-M. The neo and HSV-tk gene were cloned into vector pBluescript_SK＋ as positive and negative selective gene. [Result] Restriction enzyme digestion and sequencing results showed that mouse MSTN gene was cloned into the targeting vector pLoxP-5N3T-M. [Conclusion] The mouse MSTN gene targeting vector pLoxP5N3T-M was successfully constructed.

Increasing Accumulation Level of Foreign Protein in Transgenic Plants Through Protein Targeting

Targeting of the synthesized polypeptide in the cells is an important research field in modern cell biology. Cowpea trypsin inhibitor (cpti) gene has been modified and a fusion protein gene (sck) was produced by fusing a signal peptide sequence at cpti 5' end and an endoplasm reticulum (ER) retention signal peptide at cpti3' end respectively. The signal peptide can direct the newly synthesized polypeptide into ER, while ER retention signal can make the protein retained in the ER and its derivative protein body. ELISA test indicated that the accumulation level of foreign CpTI protein in sck transgenic tobacco (Nicotiana tabacum L.) was two times higher than cpti transgenic tobaccos and some individuals were four times higher. At the same time, sck transgenic tobacco has a high resistance to Lepidoptera pest due to the increased accumulation level of foreign CpTI protein. The strategy of foreign protein targeting can be used to increase the accumulation level of foreign protein in transgenic plants and can be widely applied to other related research field in plant genetic engineering.

Preparation of Liposomes with Palmitic-Antibody andTargeting in Vitro

An anti-trichomonas vaginalis monoclonal antiboody was derivatized with palmitic acid using an activated ester of N-hydroxysuccinimide About 50% of the re-sulting antibody could be incorporated into liposomes.The liposomes showed specific binding to T. vaginalis by IFA and cytotoxicity tests. These results clearly demonstrated the effectiveness of targeting of liposomes modified by monoclonal antibody in vitro.

PCR-Targeting体系构建棒状链霉菌基因突变株

棒状链霉菌(Streptomyces clavuligerus)可产生多种β-内酰胺类化合物,其中包括克拉维酸。利用聚合酶链式反应(PCR)-Targeting体系构建棒状链霉菌突变株是获得克拉维酸高产菌株的又一可行方法。采用该体系对棒状链霉菌的lat基因进行了敲除,获得了没有抗性标记的lat基因被敲除的突变株S.clavuligerus lat::scar,其克拉维酸产量是出发菌株的2.8倍。由于最终构建的突变株没有抗性标记,因此可以将该方法应用于突变棒状链霉菌的其他基因,实现用一种抗性标记突变同一菌株不同基因的目的,为链霉菌的基因突变提供了又一种有效的方法。

Targeting Effect Study of ￣(3) H-Mitoxantrone Nanosphereson Hepatocellular Carcinoma(HCC) Model in Nude Mice

The distribution of ￣(3)H-mitoxantrone polybutyl cyanoacrylate nanospheres(￣(3)H-DHAQ-PBCA-NS)in the viscera,muscle and tumors of human hepatocellular carcinoma (HCC)model in nude mice was studied with liquid scintillation counting techniique. The results showed that the ￣(3)H-DHAQ-PBCA-NS had remarkable liver targeting effect. The content of ￣(3)H-DHAQ-PBCA-NSin liver and heterotopic liver tumor was found to be 71.31±10. 49% of total amount of drug in animal body. It was also found that the content of ￣(3)H-DHAQ-PBCA-NS in liver was higher than that in liver tissue, and the content of ￣(3)H-DHAQ-PBCA-NS in annpit tumor was higher than that in armpit muscle tissue,but had no significant difference;It provides an ideal preparation for the DHAQ admini-stration.

A Study on the Multi-Compartment Linear Circulation Pharmacokinetic Model for the Targeting Drug Delivery System

By analyzing the observed phenomena and the data collected in the study, a multi-compartment linear circulation model for targeting drug delivery system was developed and the function formulas of the drug concentration-time in blood and target organ by computing were figured out. The drug concentration-time curve for target organ can be plotted with reference to the data of drug concentration in blood according to the model. The pharmacokinetic parameters of the drug in target organ could also be obtained. The practicability of the model was further checked by the curves of drug concentration-time in blood and target organ(liver) of liver-targeting nanoparticles in animal tests. Based on the liver drug concentration-time curves calculated by the function formula of the drug in target organ, the pharmacokinetic behavior of the drug in target organ(liver) was analyzed by statistical moment, and its pharmacokinetic parameters in liver were obtained. It is suggested that the (relative targeting index( can be used for quantitative evaluation of the targeting drug delivery systems.

Sorafenib-based combined molecule targeting in treatment of hepatocellular carcinoma

Sorafenib is the only and standard systematic chemotherapy drug for treatment of advanced hepatocellular carcinoma(HCC) at the current stage. Although sorafenib showed survival benefits in large randomized phase Ⅲ studies, its clinical benefits remain modest and most often consist of temporary tumor stabilization, indicating that more effective first-line treatment regimens or second-line salvage therapies are required. The molecular pathogenesis of HCC is very complex, involving hyperactivated signal transduction pathways such as RAS/RAF/MEK/ERK and PI3K/AKT/m TOR and aberrant expression of molecules such as receptor tyrosine kinases and histone deacetylases. Simultaneous or sequential abrogation of these critical pathways or the functions of these key molecules involved in angiogenesis, proliferation, and apoptosis may yield major improvements in the management of HCC. In this review, we summarize the emerging sorafenib-based combined molecule targeting for HCC treatment and analyze the rationales of these combinations.