Finally, abundance of functional groups enables modifying the external surface of MOF particles with stealth coating and ligand moieties for improved drug delivery. To date, there are a number of MOF-based nanomedicines available for the treatment of bacterial infections. This review is focused on biomedical consideration of MOF nano-formulations designed for the therapy of intracellular infections such as Staphylococcus aureus, Mycobacterium tuberculosis, and Chlamydia trachomatis. Increasing knowledge about the ability of MOF nanoparticles to accumulate in a pathogen intracellular niche in the host cells provides an excellent opportunity to use MOF-based nanomedicines for the eradication of persistent infections. Here, we discuss advantages and current limitations of MOFs, their clinical significance, and their prospects for the treatment of the mentioned infections.Metal-organic frameworks (MOFs) are a highly versatile class of ordered porous materials, which hold great promise for different biomedical applications, including antibacterial therapy. In light of the antibacterial effects, these nanomaterials can be attractive for several reasons. First, MOFs exhibit a high loading capacity for numerous antibacterial drugs, including antibiotics, photosensitizers, and/or photothermal molecules. The inherent micro- or meso-porosity of MOF structures enables their use as nanocarriers for simultaneous encapsulation of multiple drugs resulting in a combined therapeutic effect. In addition to being encapsulated into an MOF’s pores, antibacterial agents can sometimes be directly incorporated into an MOF skeleton as organic linkers. Next, MOFs contain coordinated metal ions in their structure. Incorporation of Fe Antibiotics are an important part of modern medicine. However, the treatment of bacterial infections still faces serious challenges owing to antibiotic resistance, which is a rapidly emerging phenomenon. According to a WHO report in 2019, antimicrobial resistance belongs to the top-10 threats to global health, leading to a reduction in antibiotic effectiveness and posing a growing challenge to global healthcare .Among bacterial infections, some pathogens have developed an ability to avoid the host immune response by persistence inside the infected mammalian cells including professional phagocytic cells. Alongside avoiding immune cells, such behavior of bacterial pathogens also provides them with additional protection from antibacterial therapeutics. Indeed, the hydrophilic nature of the most commonly used antibiotics significantly restricts their ability to cross membrane barriers, to accumulate inside the infected cells, and, therefore, to kill intracellular bacteria . The actTo increase drug accumulation inside the infected cells, numerous nanomedicine platforms have been developed over the last 20 years ,5. SimilPorous coordination polymers, also known as metal-organic frameworks (MOFs), have attracted considerable interest as a promising DDS for antibacterial agents ,7,8 Fig. MOFs arStaphylococcus aureus (MRSA), Mycobacterium tuberculosis (Mtb), and Chlamydia trachomatis (Ctr). In addition, we will discuss the advantages of MOF-based nanomedicines and the prospects of their clinical translation for the treatment of the mentioned infections.Here, we aim to discuss antibacterial effects of MOF-based nanomedicines and to overview current MOF formulations against intracellular pathogens including methicillin-resistant Antibacterial effects of MOF-based nanomedicines can be achieved via different strategies including either MOF structural units (organic and inorganic building blocks) as active agents, or an MOF porous system for therapeutic cargo delivery.Antibacterial MOFs can provide a source of metal ions, which can be toxic for intracellular bacteria. Controlled degradation of an MOF structure in body fluids results in the release of metal ions from metal nodes and their interaction with bacteria cells.+, Cu2+, Co2+, Zn2+, Fe3+, Ni2+, Pb2+, and others . T. TStaphyMycobacterium tuberculosis (Mtb), which is a highly infectious acid-alcohol-resistant bacilli. Initially Mtb infects alveolar macrophages and avoids digestion in macrophage phagosomes (Tuberculosis (TB) is an infectious chronic disease caused by rod-shaped bacillus agosomes  due to iAlthough pulmonary infection is the most common kind of TB, this disease may extend to other parts of the body (extra-pulmonary tuberculosis), including the kidneys, bones, joints, circulatory system, central nervous system, and lymphatic system . Even thMost anti-TB agents have limited intracellular penetration and poor metabolic stability that leads to inefficient drug delivery and often requires extended treatment durations and/or increased doses of antibiotics . As a reIn response to the global tuberculosis pandemic and the emergence of drug-resistant tuberculosis, effective drug delivery methods have been developed in recent years along with anti-TB drugs.Using nanocarriers in the treatment of TB holds promise to improve therapeutic efficacy, decrease drug resistance, and enhance bioavailability of therapeutic candidates. As a DDS platform, MOF particles exhibit multiple attractive properties, including the ability to encapsulate multiple therapeutic payloads, as well as intracellular drug delivery to the infected macrophages. This section describes several MOF-based nanomedicines developed for TB therapy.w/w) drug loading. INH@MIL-100(Fe) nanoparticles exhibited a sustained release profile for INH  without a burst release. Similarly, Uthappa et al. . . 103]. IIn recent years, a number of antibacterial nanomedicines have been developed and tested on cell and animal models indicating their improved drug delivery and therapeutic effects in comparison with free drugs . Some of2/3+, Cu2+, Mn2+, or Zn2+ ions might contribute to the antibacterial effect of the drug cargo.To provide an unbiased evaluation of MOF-based nanomedicine prospects for the treatment of intracellular infections, it is necessary to determine their advantages as compared with widely used polymeric and liposomal nanomedicines. It is not possible to utilize one random MOF to deliver many different drugs efficiently compared with other nanomaterials, as the performance of MOFs as DDS can be dramatically influenced by the size and nature of the drug. The unique chemical and physical properties of MOFs can be designed to optimize loading compacity and drug release profiles. Similar to lipid- and polymer-based DDSs, MOF nanoparticles can also internalize and accumulate in close proximity to intracellular pathogens. As for biodistribution behavior upon systemic administration, MOF particles encounter the same concerns as other nanomaterials. However, as opposed to polymers and lipids, MOFs are not simple drug carriers. The ability to incorporate metal ions into the MOF structure allows for imparting them with innate antibacterial toxicity, which does not rely on metabolism interference. As a result, metal ions such as endogenous FeAs for the optimal administration route of MOF-based nanomedicines, local administration seems to be a safer and more reliable method for the treatment of intracellular infections. Ctr and Mtb occupy the intracellular niches in mucus tissue and lung alveoli, respectively, which are potentially achievable by local administration. MRSA-induced abscesses or MRSA-infected wounds can also be treated by the local injection of MOF-based nanoparticles, while for the treatment of sepsis only the intravenous route is reasonable. It should be noted that safety requirements for nanomedicines designed for systemic injection are stricter in terms of colloidal stability, size uniformity, and stealth coating. Despite these challenges, the production of MOF-based nanomedicines that meet these requirements is essential for ensuring their clinical effectiveness. However, scaling issues pose a significant obstacle to the cost-effective production of such nanomedicines. The same problem might also be applied to some multicomponent nanoformulations (≥3 components) described here, as a complex multi-stage synthesis procedure always significantly increases the costs and risks of nanoformulation production with each additional step. Therefore, industrial production of such nanomedicines is reasonable only when they exhibit outstanding clinical effectiveness, leading to complete pathogen eradication. In order to achieve this goal, it is necessary to optimize production procedures and explore alternative synthesis methods that are both efficient and cost-effective, while maintaining high standards of safety and efficacy.2) [Although great progress has been made in the antimicrobial performance of MOFs, the development of treatment platforms based on versatile nanoMOFs is currently in the early phase of investigation. Therefore, much more effort should be made towards clinical translation of MOFs. As mentioned above, MOF nanoparticles can reach the sheltered intracellular bacteria. However, the efficacy of MOF accumulation in bacteria-containing cell compartments remains unclear. To evaluate the sufficiency of bacterial “targeting” and therapeutic effect, multiple studies with diverse in vivo models are desired. Moreover, the development of approaches to enhance the antibacterial selectivity of MOF-based nanomedicines is also necessary. Ideal MOF-based nanoformulations should be nontoxic for mammalian cells, based whenever possible on endogenous metals and/or ligands and/or be easily decomposed and excreted without adverse effects for the host after the killing or inhibition of bacteria. Furthermore, the optimization of current MOF synthesis procedures, and particularly the development of green chemical synthesis, would help to avoid harsh fabrication conditions, as recently reported for the scalable one-pot green ambient pressure preparation of nanoMOFs formulations involving biocompatible MOFs , ZIF-8, UiO-66-NH2) ,106, andAlthough promising, the clinical use of MOFs to treat infections is still a long-term goal. We are firmly convinced that significant advances in MOF fabrication and cargo loading, as well as tuning their biodegradation behavior and selectivity, will accelerate over the near future for their practical use in the treatment of intracellular infections.


Extracellular vesicles (ECVs) have been abandoned as bio-inspired drug delivery systems (DDS) in the biomedical field. ECVs have a natural ability to cross over extracellular and intracellular barriers, making them superior to manufactured nanoparticles. Additionally, they have the ability to move beneficial biomolecules among far-flung bodily cells. These advantages and the accomplishment of favorable in vivo results convincingly show the value of ECVs in medication delivery. The usage of ECVs is constantly being improved, as it might be difficult to develop a consistent biochemical strategy that is in line with their useful clinical therapeutic uses. Extracellular vesicles (ECVs) have the potential to enhance the therapy of diseases. Imaging technologies, particularly radiolabelled imaging, have been exploited for non-invasive tracking to better understand their in vivo activity. According to several studies carried out over the years, different cellular types produce little lipid particles that act as a mirror of the activities that take place inside the cells. Since ECVs are more complex than they first appear to be, they have been divided into groups based on their size, metabolic make-up, and cell of origin . WhateveAs a nominally aggressive synthetic drug delivery deployment approach has been devised to daze restrictions of the unrestricted therapeutics and overcome diverse biological blockades across patient diseases and populations, tailored clinical interventions are becoming more and more essential for therapeutic efficacy. Nanoparticles have been developed as a delivery method to enhance the issuance or spreading therapeutic model, with a focus on controlling the intervention through the attributes of the vehicle rather than the physicochemical properties of the drug molecule . The useThe potential for ECVs or exosomes (200 nm) to serve as therapeutic nanomedicines has been studied among the many ECV subtypes ,28. By mFor SPECT and PET applications, ECVs have been labelled with a variety of techniques using radionuclides that release gamma rays or positrons. The most popular technique for radiolabelling ECVs is surface or membrane radiolabelling. This enables the radionuclide to be matched to the proteins of the membrane directly or indirectly via the formation of covalent chemical bonds. To accomplish this, the four tactics displayed below were applied. The four mechanisms of radioactive attachment are genetic adjustment, direct consolidation of radionuclides out of membrane proteins, direct integration into membrane proteins, or radionuclide adhesion via chelator  on the surfaces A. Radion(i)High sensitivity: surface radiolabelling can achieve high sensitivity, allowing for the detection of low concentrations of exosomes.(ii)Specificity: surface radiolabelling can provide high specificity by labelling only the surface of exosomes, thus avoiding interference from intracellular components.(iii)Non-invasive: surface radiolabelling is non-invasive and does not require the use of antibodies, making it an attractive labelling method for clinical applications.(iv)Easy to perform: surface radiolabelling is a simple and straightforward technique that can be performed with minimal sample preparation.(v)Versatility: surface radiolabelling can be used in a variety of downstream applications, including imaging, quantification, and tracking of exosomes in vitro and in vivo.Surface radiolabelling of exosomes, which involves the labelling of exosomes with radioactive markers on their surface, has several advantages including, but not limited to:(i)Radioactive waste: the use of radioactive isotopes for labelling exosomes can generate radioactive waste that must be carefully managed and disposed.(ii)Limited specificity: surface radiolabelling of exosomes is based on the labelling of surface proteins, which may not necessarily represent the entire exosome population. This technique may not be specific to a particular protein of interest, as it could also label other proteins that are not relevant to the study.(iii)Potential alteration of exosome behaviour: the labelling process can potentially alter the behaviour and properties of the exosomes, leading to inaccurate results in downstream assays.(iv)Inability to study internal components: surface radiolabelling only labels the external components of exosomes and, therefore, cannot provide information about the internal contents of the vesicles.(v)Inability to track exosome movement: surface radiolabelling is a static labelling technique and does not allow for the tracking of exosome movement or dynamic behaviour.Surface radiolabelling of exosomes involves the use of radioactive labels to tag exosome proteins on their surface. While this technique has been widely used in exosome research, it has some limitations that should be considered. These include:In conclusion, surface radiolabelling of exosomes has some limitations that should be considered when interpreting results. Alternative labelling and tracking techniques such as fluorescent labelling, mass spectrometry, and electron microscopy can provide complementary information to surface radiolabelling .99mTc]-Tc-hexaoxime ([99mTc]-Tc-HMPAO)  Zr (oxinate)-4 (a corpus or liposome radiotracer) for prompt or intra-luminal radiolabelling of distinct ECVs was examined by Khan et al., (2022) ..111IndiuThe ECVs’ volatility is one of the main obstacles to in vivo imaging. According to a study by Clayton et al., (2003) , ECVs haThe dimensions and integrity of exosomes (EXOs) were unaffected by additional chemical engineering, with the exception of chemical transfection and the previously stated saponin-incorporated drug freight on the exosomes (EXOs). An a, b-unsaturated carbonyl reacts with an enolate-type nucleophile in the Michael addition. It has been used for a long time in organic synthesis to create highly selective compounds in a safe manner . ChemicaNumerous studies have shown that EXOs are being modified via chemical engineering to function as “bioscaffolds” for medical diagnosis and treatment. For the early-stage diagnosis of malignancy, the detection of intact EXOs is essential because they behave as desirable substitutes for certain tumor cell-associated counterparts . In a reExosomes are typically labelled with different lipophilic fluorescent dyes or luminous probes in order to assess their in vivo properties. In Wiklander et al., (2015)  and PeinThe process through which a substance emits light without requiring or producing heat is known as luminescence. In order to monitor exosomes, numerous aptasensors based on luminescence have been created because of their great sensitivity, because they are relatively inexpensive, and because they are simple to control. Electrochemiluminescence and luminescence resonance energy transfer (LRET) are the two kinds of luminescence that are distinguished here based on the energy source (ECL).Aptasensors depending on LRET display the same positive effects of high sensitivity, excellent operability, and resolution as the FRET mechanism. Therefore, utilizing rare earth incapacitated up-conversion nanoparticles (UCNPs) that are transformed into gold (Au) nanorods is essential. Chen and colleagues (2018)  created The ECL approach, in contrast to electrochemical exploration, does not rely on external parameters, including temperature, electrode surface roughness, pH, humidity, and many more. Qiao et al., (2019)  created On paper-based portable devices, the aptasensor, lateral flow-strip (LFS) is frequently used and has a simple user interface and color and signal change makes the outcome clear. LFS is frequently separated into 2 categories of pack strip, with either competitive strip grounded on various exchanges onto test lines . Based on thermal signals, Cheng et al. created a sandwich strip for exosome identification. Yu et al., (2020)  suggesteSERS has a constrained spectral bandwidth and distinctive fingerprint properties for distinguishing different exosomes. MB-capture substrates by utilizing diverse aptamer probes. Wang et al. advanced a SERS aptasensor for simultaneous finding of multiple exosomes . To collSPR is an approach to ocular biosensing that can be utilized to observe in-situ and real-time biomolecular interactions on metal surfaces. This technique doesn’t require any markers and doesn’t harm biomolecules in any way. For the purpose of exosome detection and dual AuNP-assisted signal amplification, Wang et al. used the SPR aptasensor for exosome uncovering, then dual AuNP-aided signal amplification . In orde2-Fe3O4 nanostructures (MOFE). On the GMR sensor surface, the CD63 aptamer was modified for widespread exosome capture. To recognize exosomes, MOFE-labelled aptamer probes were used. This pack of “GMR/CD63 aptamer-exosome-MOFE/detection aptamer” greatly increased the signal of GMR   establisl of GMR .(1)Natural dyes: the surface of the exosome lipid bilayer receives the fat chain through the lipophilic organic dye. This characteristic makes it possible to prolong and stabilize the fluorescence of the fluorescent dye. In addition, the fluorescent dye’s emission spectrum, which extends from 502 from 734 nm, has a broad application window with great selectivity. However, the fluorescence quantum yield, half-life, light color, and other properties of this organic dye differ between dyes. Moreover, variations among dyes may involve the mutual reinforcement of other liposomes through dyeing, which will contribute to imprecise results .(2)Fluorescent proteins that are genetically encoded: red and green fluorescent proteina, as well as other fluorescent proteins fall under this category. Through the use of gene editing technologies, they are alluded to as marker proteins found on the superficial exosome. To assess the in vivo and in vitro movement and metabolic transfer of exosomes and prevent other liposomes from being mislabelled, one of the exosome markers, CD63, was frequently fused with them .(3)Reporter molecules that are immunofluorescent: the highly specific immunofluorescence labelling technique involves colouring the exosome first, then the antibody with an organic dye. The need for microscopy equipment is quite high because exosomes are so tiny. Due to their increased resolution, stochastic optical reconstruction microscopy and photoactivated localization microscopy were better suited for observing exosomes .(4)Nanomaterials that glow: due to their tiny size and superior optical qualities, fluorescent nanoparticles are uncomplicatedly bound and don’t affect the physiological activity of exosomes in any significant way. However, there is a great mandate for near infrared (IR) fluorescent nanoprobes including deep tissue dissemination and negligible autofluorescence background tracking . The priThrough in vivo and in vitro research, real time drug delivery systems must be watched to demonstrate the drug’s structure, concentration, and timing of arrival at the target site. Animal application experiments require the tagging and monitoring of exosomes. The exosomes of sick tissues were observed using computer tomography (CT), fluorescent bioluminescence imaging, microscopy, and magnetic resonance imaging (MRI) . FluoresOne study electroporated SPIONs into exosomes . Researc111indium-DTPA, bioengineering with fluorescent (mCherry) or bioluminescent (luciferase) proteins, and a commercially available iron oxide nanoparticle (Feraheme). The study concluded that none of the labelling methods significantly influenced the biodistribution of ECVs when compared to the control group that was not labelled. However, covalent labelling could potentially affect the functionality of ECVs, and further investigation is required to determine the most suitable labelling technique for different ECVs applications [In research conducted by Lázaro-Ibáñez, the impact of five different tracers on the biodistribution of extracellular vesicles (ECVs) in vivo was investigated. The aim was to develop ECVs as effective drug delivery vehicles and therapeutic agents while being able to track them without disturbing their biodistribution. The tracers evaluated included a noncovalent fluorescent dye (DiR), covalent modification with ications  -based immunotherapy and tracking of DC migration to lymph nodes. Gold nanoparticles modified with oligonucleotides were used for PET/CT imaging, which showed higher radio sensitivity and allowed for long-term monitoring of DC migration to lymph nodes. In vivo experiments on mice immunized with Lewis lung carcinoma demonstrated strong antitumor immunity for lung cancer without any adverse effects on the biological function of dendritic cells. These findings suggest that radionuclide-embedded gold nanoparticles have the potential to be an effective tool for cancer immunotherapy .131I, which is attached to the gold nanoparticles using the Iodogen method. The resulting system is designed to selectively target and treat lung cancer cells expressing EGFR, while also allowing for the imaging and monitoring of the tumor. The in vivo study conducted on tumor-bearing mice showed promising results, including anti-proliferative activity and radioactive retention in the tumor, indicating the potential of the system as an effective nano theranostic for EGFR-expressing lung cancer [The study also involves the creation of a hybrid system for the treatment and diagnosis of lung cancer, which utilizes PEGylated gold nanoparticles to target EGFR. Cetuximab is also conjugated to the gold nanoparticles for therapeutic purposes. Radio-immunotherapy is employed using the radioisotope g cancer .Researchers studied the potential of a hybrid theranostic nanosystem to precisely locate and diagnose vulnerable atherosclerotic plaques by targeting apoptotic macrophages. They used gold nanoparticles that were radiolabelled with 99mTc and conjugated with Annexin V as targeting molecules, which were synthesized through a chelation method. The nanosystem was evaluated using SPECT/CT imaging, and promising results were obtained, indicating its potential as a tool for identifying and assessing vulnerable atherosclerotic plaques .64Cu to image primary tumors and lung metastases in a mouse model of 4T1 orthotopic breast cancer. The PET imaging results obtained after administering the developed formulation demonstrated accurate detection of CXCR4 up-regulation, which confirmed the nanoclusters’ targeting specificity. Therefore, the study concluded that this approach holds promise as a diagnostic tool for early and accurate diagnosis of breast cancer with lung metastasis [50 compared to DOX alone. While these results are promising, it is important to note that further studies are necessary to assess the safety and efficacy of this system in humans, including in vivo studies and clinical trials [This study utilized gold nanoclusters that were modified with AMD3100 (plerixafor) and labelled with tastasis . Gallic l trials .68Ga using a chelator-free method for imaging pre-operative and intraoperative profiles in lymph node disease using PET imaging. This technique shows promise for improving the accuracy and sensitivity of imaging in lymph node disease, thereby aiding in more effective treatment planning and monitoring.The field of nanotechnology has made significant strides in the synthesis and physicochemical properties of magnetic nanoparticles, which have proven to be attractive candidates for various biomedical applications. Magnetic nanoparticles offer high surface area and improved quantum efficiencies, making them useful as nanocarriers for molecular imaging and therapeutic applications. Moreover, the release of drugs from these nanoparticles can be readily modified using external fields such as magnetic or NIR radiation. Another promising application of nanoparticles is in Surface Enhanced Resonance Raman Scattering (SERRS), which enables accurate detection of malignant or premalignant lesions and non-invasive imaging of the whole body. In light of these advantages, researchers have developed SERRS nanoparticles labelled with 69Ge on the nanoparticles without the use of a chelator. The results showed that PEGylated SPIONs accumulated over time in tumor cells and were found to be safe and biocompatible for use in hybrid imaging and therapy for cancer [68Ga chelator, NOTA derivative, which is coupled with the GEBP11 peptide. Immunofluorescence and Prussian blue stains were used to demonstrate the peptide’s affinity, indicating its potential in visualizing plaque formation [The study aimed to investigate the passive targeting efficiency of 64Cu-labelled PEGylated and reduced graphene oxide-iron oxide (GO-IO) nanoparticles via the Enhanced Permeability and Retention (EPR) effect, using photoacoustic and PET imaging techniques. The in vivo study was conducted on a hind limb ischemia model, which demonstrated that the hybrid radiolabelled metallic nanoparticles were able to effectively target the ischemic tissue through passive targeting via the EPR effect, as evidenced by clear visualization of the nanoparticles in the affected area . Researcr cancer . The stuormation .188Re for tumor targeting. The results demonstrated that 188Re provided radiotherapy and SPECT/CT imaging in a VX2 tumor model. Additionally, the peanut-shaped nanoparticles showed higher tumor uptake than spherical-shaped nanoparticles [Silica nanoparticles are popular for drug delivery and bio-imaging due to their advantages, but they have some drawbacks. In a recent study, researchers developed mesoporous silica nanoparticles with MUC1 aptamer capping, loaded with safranin O, and functionalized with aminopropyl groups for controlled drug delivery and tumor imaging. The system demonstrated higher tumor uptake of nanoparticles in mice, showing a promising approach for simultaneous drug delivery and imaging . The stuarticles . The stuarticles . A dual-articles .64Cu using DOTA as a chelating agent and conjugated with target-specific peptide RGDyK for tumor localization using PET imaging. Additionally, 89Zr-radiolabelled HPMA polymeric conjugates were prepared for therapeutic efficacy on a 4T1 cancer cell model. The study found that the disparity and molecular weights of the polymer played a significant role in the pharmacokinetic profile of polymeric conjugates. Furthermore, higher molecular weight polymeric carriers showed higher cellular uptake and cytotoxicity in vitro [90Y isotopes for targeted radiotherapy of neoplastic cells. The nanoconjugates induced higher apoptosis in the targeted cells with no side effects on off-targeted tissues. These findings suggest that HPMA copolymer conjugates have potential for targeted radiotherapy in cancer treatment [64Cu and loaded with the antitumor drug docetaxel and the anti-inflammatory agent curcumin. The system was stabilized with Egg PG and PEGylated DSPE-PEG-COOH. PET/CT imaging was used to monitor the response to therapy. Results showed a synergistic effect when both drugs were delivered together, with 100% of mice surviving, compared to only 50% with DTX alone [89Zr and 177Lu were developed as a theranostic system for cancer. The nanostars showed higher accumulation in tumors and improved survival rates in mice, indicating their efficacy in passive targeting via the EPR effect [18F and used for PET imaging. The nanocarriers showed higher uptake in HeLa cells and successful in vivo tumor imaging using PET and NIRF labelling [Polymeric nanoparticles have become popular for radiotheranostic applications in diseases such as cancer, diabetes, and neurological disorders. Radiolabelling can be done through pre- or post-labelling strategies using chelators or cross-linking agents. A recent study used radiolabelled HPMA nanoparticles loaded with antitumor drugs to evaluate their efficacy in an in vivo tumor model, showing improved accumulation in tumor cells, longer circulation time, and a higher therapeutic index with the combination of radiotherapy and chemotherapy . The stuin vitro . The stureatment . ResearcTX alone . PolymerR effect . Lactosoabelling . Researcabelling .The study of extracellular vesicles (ECVs), used as nanomedicine gadgets, has recently attracted the attention of a large number of researchers. Insight into ECV biology and behaviour may surely be gained by employing imaging modalities, presumably optical or radionuclide-based. This is plainly obvious from the research that has been done thus far. These techniques ought to be incorporated into facilitating their early development as possible treatments or diagnostic instruments. The radiolabelling techniques used and the results from SPECT/PET imaging were the main topics of this review. This research used intraluminal and membrane-based radiolabelling techniques, which fall into two primary types.Our analysis highlights the significance of selecting the best radiolabelling technique for downstream application because each has benefits and drawbacks. This embraces the perks of incorporating in vivo ECV studies including envisioning with radionuclides, which have excellent sensitivity and quantification capabilities. This will help us better understand the fundamentals of these subgroups’ ECV biology, including their interactions with other cells and organs.Additionally, the ability to evolve/optimize the strategy for foreseeable future clinical investigations is provided by the imaging modality’s availability in clinical settings. In this study, we have described numerous radiolabelling methods for biomedical applications of radioisotopes to ECVs. Several of the approaches are addressed, including covalent binding, intraluminal labelling, and membrane radiolabelling.We highlight important elements such as radiolabelling effectiveness and stability in biological contexts since they are essential for an extensive depiction of how ECVs behave in real life throughout the course of their biological half-life. In the constantly developing field of nanotechnology, the approaches affirm how molecular envisioning with PET including SPECT can facilitate the ECVs biological creation for medical prognosis, including therapy. Exosomes hold great therapeutic potential, and numerous tracking techniques have been created to investigate their operation. Future research could use artificial intelligence, including machine learning, to scrutinize these data which determine whether the exosome movements indicate a low or high possibility of the therapy’s accomplishment quickly after treatment with exosomes is initiated, with the aid of the right imaging modalities.Exosomes may be used to distribute drugs in a targeted manner in the future as more research results in a better knowledge of their biological functions. They would be able to treat particular patients with care for their unique needs while battling a variety of ailments. We will be able to create an expanded understanding of their capabilities and limitations with the help of an upcoming study, which is certain to occur.


The brain-computer interface (BCI)-mediated rehabilitation is emerging as a solution to restore motor skills in paretic patients after stroke. In the human brain, cortical motor neurons not only fire when actions are carried out but are also activated in a wired manner through many cognitive processes related to movement such as imagining, perceiving, and observing the actions. Moreover, the recruitment of motor cortexes can usually be regulated by environmental conditions, forming a closed-loop through neurofeedback. However, this cognitive-motor control loop is often interrupted by the impairment of stroke. The requirement to bridge the stroke-induced gap in the motor control loop is promoting the evolution of the BCI-based motor rehabilitation system and, notably posing many challenges regarding the disease-specific process of post stroke motor function recovery. This review aimed to map the current literature surrounding the new progress in BCI-mediated post stroke motor function recovery involved with cognitive aspect, particularly in how it refired and rewired the neural circuit of motor control through motor learning along with the BCI-centric closed-loop. Recovery of motor function is of significant importance for physical independence and social integration of stroke patients. One of the ambitions of post stroke motor function restoring (PMFR) is to recouple the brain and external muscles while supporting the patients' personhood by regaining functional activities of daily living  rather than replacing incomplete limbs with lifelong prostheses Kübler, . It is w“The cortical motor system is not an unthinking, passive circuit controlled by more intelligent parts of the brain , cingulate motor areas (CMA), premotor areas (PMA)] in the frontal lobe and parietal lobe are wired together to participate in motor control during self-paced movements  has been recognized as an association cortex in the sensorimotor pathway. The PPC is involved in motor intention, movement planning, spatial reasoning, and integration of multisensory feedback that is transmitted to the frontal lobe for movement control. Damage to the PPC from stroke can impair the patient's ability to plan movements and perceive spatial relationships that affect sensorimotor circuitry  has been the most extensively studied and reported in the literature. The emotional changes in stroke patients can be a result of the brain physical damage to the mood regulation systems , functional magnetic resonance imaging (fMRI), magneto-encephalo-graphy (MEG), and near-infrared spectroscopy (NIRS), while invasive methods include electrocorticogram (EcoG) and intracortical decoding with penetrating electrodes , θ (4–7.5 Hz), α (8–13 Hz), β (13–30 Hz), γ (30–100 Hz). Of these bands, the most important for movement decoding is the oscillation in the alpha band in sensorimotor cortex, also known as μ-rhythm  during mental simulation of left-handed movements  has been used for signal acquisition during BCI operation, benefiting from its high spatial and spectral resolution . However, the conductive gel will dry out within a few hours, making the performance of the electrodes become unstable over time  has gained prominence among post-stroke motor rehabilitation topics in recent decades, especially for robotic procedures. In stroke patients, the damaged motor network may prevent the BCI from decoding the motor signal in real time. Nevertheless, the MI process has a similar neural basis as the real motor performance  or decreased  the cortical excitability. Although there is a potential risk of epilepsy with the use of rTMS in the acute phase of stroke, more positive effects of rTMS on motor recovery have been observed in recent studies Kubis, . It is tIn tDCS, weak direct electrical currents are used to alter the firing threshold of the neuronal membrane in specific parts of the brain, modifying spontaneous activity. Depending on the direction of the current , it can decrease or increase cortical excitability , have been developed as independent and passive machines to perform therapies that require high intensity repetition. However, as the effector node in closed-loop BCI, these external devices can be controlled by stroke patients through the BCIs, according to the assistive and rehabilitative needs of the users  exoskeletons for the restoration of the functions of limbs and (ii) neuro-prostheses for replacement of the disabled limbs. However, for PMFR, a device to restore limb motor function by helping the motor cortex to acquire motor control function through motor learning is more important than a replacement of limbs. It has been shown that repetition and prolonged training can be beneficial for the recovery of limb strength, but have little effect on the reorganization of the cortical map  to the limbs of the user. However, which feedback would be most important and how this feedback should be provided is still under investigation. Nevertheless, in stroke patients with impaired proprioception and tactile sensation, the missing sensory information can be compensated by the feedback, which is important both for the completion of a specific task and for the recruitment of the motor control circuit  close the sensorimotor loop with self-regulation, thus facilitating the control of external assistive robotics (ii) activate the plasticity system, thus promoting the reorganization of the motor cortex. The neurofeedback can induce endogenous neural stimulation to facilitated motor output. For example, the same object can evoke different voluntary actions through its physical properties and the behavioral salience observed by the observer. The somatic sensory input from body receptors can be a teaching signal during motor learning, presenting as feedback-error learning and supervised learning. Learning a motor skill can continually reorganize or shape a stroke survivor's motor map. Animal and human experiments have demonstrated that neural activity can be self-regulated through neurofeedback. A prevailing closed-loop modality for BCI-mediated PMFR is often based on non-invasive EEG, it involves three steps: (i) EEG collects neural activation signals in the M1 region to control the surrounding prostheses or exoskeletons, (ii) terminal devices performance generate behaviors as the source of feedback to change the firing rates of a population of cortical neurons, (iii) learned control of multiple neurons is presented simultaneously to regulate EEG amplitudes, which enhances internal processing to facilitate control of the external device or paretic limb motor activity during task-specific actions  that provides the patient himself the information on how good his performance of the MI tasks  is an immersive computer-based technology that places the user in simulated environments with real objects and events. There is growing evidence that VR may promote PMFR in combination with both conventional therapy and BCI-mediated therapy  Understanding Compensatory Motor Control Mechanisms in Post-Stroke Patients: Existing research has provided insights into compensatory motor control mechanisms in post-stroke patients, such as neural reorganization and adaptive processes. However, future research should delve deeper, utilizing tools like neuroimaging, biosensors, and computational models to precisely identify and quantify these mechanisms. Integration of these findings into the BCI system will be crucial for achieving more effective motor rehabilitation. (2) Customizing Multimodal Feedback for Individual Patients: In current research, efforts have been made to explore the customization of multimodal feedback based on individual patient conditions and needs. These customization methods can adapt feedback based on the emotional state, sensory abnormalities, and cognitive function of patients. Leveraging machine learning and patient-specific data, such as neural signatures and behavioral responses, will enable a more personalized approach to BCI-mediated PMFR. (3) Advancements in BCI-Compatible Brain Stimulation Techniques: Significant progress has been made in developing BCI-compatible brain stimulation techniques. These techniques leverage neurofeedback and real-time monitoring to optimize stimulation timing and intensity. Additionally, advancements in non-invasive brain stimulation modalities, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), are becoming increasingly integrated into BCI systems for neuroplasticity induction. (4) Enhancing Brain Motor Signal Extraction Techniques and Devices: Recent research has focused on improving brain motor signal extraction techniques and devices. Advanced signal processing algorithms, including deep learning approaches, have reduced noise and enhanced signal reliability. Portable and wireless EEG  devices are now more accessible, allowing for real-world applications of BCI-mediated PMFR with greater convenience and improved signal quality. (5) Developing Customized Soft, Wearable Exosuits: Research has led to the development of soft, wearable exosuits tailored to individual functional needs. These exosuits incorporate flexible materials and ergonomic designs to ensure comfort and ease of use. Integration with BCI technology involves optimizing the communication interface between the exosuit and the BCI system, allowing for seamless control of assistive devices tailored to each patient's motor rehabilitation requirements.JM: Writing—original draft. ZX: Writing—original draft, Writing—review and editing. YQ: Writing—review and editing. TZ: Methodology, Writing—original draft, Writing—review and editing.


Regenerative repair of the brain after traumatic brain injury (TBI) remains an extensive clinical challenge, inspiring intensified interest in therapeutic approaches to explore superior repair strategies. Exosome therapy is another research hotspot following stem cell alternative therapy. Prior research verified that exosomes produced by neural stem cells can participate in the physiological and pathological changes associated with TBI and have potential neuroregulatory and repair functions. In comparison with their parental stem cells, exosomes have superior stability and immune tolerance and lower tumorigenic risk. In addition, they can readily penetrate the blood‒brain barrier, which makes their treatment efficiency superior to that of transplanted stem cells. Exosomes secreted by neural stem cells present a promising strategy for the development of novel regenerative therapies. Their tissue regeneration and immunomodulatory potential have made them encouraging candidates for TBI repair. The present review addresses the challenges, applications and potential mechanisms of neural stem cell exosomes in regenerating damaged brains. Exosomes are phospholipid bilayer membrane structures with a 40–100 nm diameter that are secreted from almost all mammalian cells. Initially, researchers believed that exosomes are waste products released by cells, but subsequent studies found that information exchange between cells is closely related to exosomes . ExosomeAs the “headquarters” of human functional activities, the regeneration and repair of the brain after injury is a problem in today’s scientific community. The fact that brain neurons have the genetic characteristic of being difficult to regenerate and the inhibitory microenvironment after traumatic brain injury (TBI) are key difficulties in neurological repair. Therefore, the focus of functional recovery after TBI is based on promoting neuroregeneration after injury and creating a suitable microenvironment. Growing evidence has proven that the use of stem cell-derived exosomes can confer more benefits in treating TBI than directly transplanting stem cells, creating new therapeutic pathways for nerve regeneration , 22. CurNeural stem cells (NSCs) are self-renewing, differentiating and proliferating cell populations that can improve neurological function by stimulating vascular regeneration and neuroregeneration and repair. Current sources of neural stem cells fall into two categories, each with its own strengths and limitations. The first includes endogenous neural stem cells that are mainly distributed in the subventracular zone (SVZ) of the lateral ventricle and subgranular zone (SGZ) of the dentate gyrus of the hippocampus  and the The complexity and practical issues of NSC treatment described above prompted us to explore other treatment strategies that can exert effects similar to those of NSCs. Because of the continuous deepening of stem cell research, growing evidence has demonstrated that cell substitution is not the primary mechanism of NSCs, but relies on the paracrine utility of NSCs . NSCs reExosomes are small vesicles secreted by cells that carry biological information and are produced via endosome and plasma membrane pathways. Exosomes can not only be used as biomarkers for the diagnosis and treatment of diseases, but also serve as a major medium of intercellular communication. In addition, exosomes play a critical role in the transport of membrane cells to cytoplasmic proteins, lipids and ribonucleic acid (RNA) . The bioExosomes are rich in lipids, proteins, nucleic acids and other biologically active substances, which play a vital role in regulating cell physiological functions and affecting intercellular information transmission. It is generally believed that exosome components may differ depending on their origin and cell type. Exosomes have been identified as containing 4563 proteins, 764 miRNAs, 1639 mRNAs and 194 lipids . StudiesNotably, human neural stem cells (hNSCs) express c-MYC protein, a marker of NSCs, in addition to the proteins CD63 and CD81, which are common markers of exosomes. Second-generation sequencing showed that the miRNAs contained in hNSC exosomes were different from those from other sources. There were 113 kinds of miRNAs secreted by hNSCs, among which five kinds of miRNAs, including hsa-miR-1246, hsa-miR-4488, hsa-miR-4508, hsa-miR-4492 and hsa-miR-4516, were highly expressed . As one We can identify exosomes by detecting surface marker proteins, morphology and particle size. Common methods for surface marker detection mainly include western blotting, enzyme-linked immunosorbent assay, immunofluorescence staining, flow cytometry analysis and mass spectrometry . We usuaAs a cardinal communication medium in cells, exosomes can bind to target cells in different pathways to transmit information. Currently, it is generally considered that the biogenesis of exosomes mainly involves plasma membrane and endosome pathways. In the endosome pathway, early endosomes bud from the plasma membrane to form early endosomes; subsequently, early endosomes germinate intraluminal vesicles (ILVs) to form multivesicular bodies (MVBs), and finally, MVBs fuse with the plasma membrane to release exosomes. In addition, some evidence has been corroborated that exosomes can bud directly from the plasma membrane, namely the plasma membrane pathway. Currently, the most studied biogenesis pathway of exosomes is the endosomal pathway. Cytoplasmic membrane invagination can form early endosomes, and early endosomes (Rab5 as a marker) mature to late endosomes (Rab7 as a marker) through acidification and material exchange. Late endosomes can finally form MVBs containing ILVs that are constituted by budding inwards depressions from the multivesicular membrane. Polyvesicles are degraded by fusion with lysosomes or autophagic lysosomes, and fusion with the cytoplasmic membrane results in the secretion of luminal vesicles outside the cell and ultimately forms exosomes with a diameter range from 40 to 160 nm Fig. .Fig. 2ScThe endosomal pathway is currently the most widely studied mechanism of exosome genesis. Early endosomes gradually mature into MVBs, and the formation of MVBs has two mechanisms: endosomal sorting complex required for transport (ESCRT)-dependent and ESCRT-independent mechanisms. ESCRT, an essential machinery, comprises four various protein complexes: ESCRT-0, ESCRT-I, ESCRT-II, ESCRT-III and the associated AAA ATPase Vps4 complex . The ESCDue to their small size, low density and being mixed with similar components, the separation of exosomes poses a great challenge to their separation. Common separation methods of exosomes secreted by NSCs and other cells mainly include ultracentrifugation, ultrafiltration and size exclusion chromatography, polymer precipitation, immunoaffinity capture chromatography and microfluidic chip separation –54. AmonFor the storage conditions of exosomes, it is also extremely vital to be able to maintain the integrity of exosomes in vitro. Some studies have suggested that different storage conditions may affect exosome size but do not have much impact on the cargo carried by exosomes. The data showed that exosome size decreased by approximately sixty percent after two days of storage at 37 °C. The exosome size remained basically unchanged after two days of storage at 4 °C, while the exosome size decreased significantly after 3 ~ 4 days. Interestingly, the morphology and size of exosomes can be maintained for one month when stored at − 20 °C . AnotherExosomes secreted by NSCs are involved in a wide range of interactions between neurons and microglia in the central nervous system . MoreoveExosomes derived from NSCs participate in the function and development of many physiological and pathological conditions of central nervous system diseases. NSC-derived exosomes are rich in specific miRNAs that can communicate with the microenvironment, mediate viral entry into cells and function as independent metabolic units . PreviouA previous study demonstrated that NSCs are expected to become an efficient strategy for TBI treatment in both experimental models and clinical practice , 67. NevThe complex pathophysiological mechanism caused by TBI eventually leads to primary neuronal damage and delayed neuronal damage, which is mainly manifested in the programmed death of neurons.In the brain, neurons, astrocytes, microglia, vascular endothelial cells, vascular perivascular cells, the basement membrane and the extracellular matrix make up the neuronal vascular units . A serieResearch has revealed that exosomes secreted by NSCs are involved in a wide range of interactions between neurons and microglia in the CNS and participate in brain injury repair . In addiNeuroinflammation has proven to be a crucial part of the pathophysiological process of TBI. Its pathological changes mainly include glial cell activation, upregulation of proinflammatory cytokines, increased inflammatory cell infiltration and increased blood and brain barrier permeability . As inflInflammatory modulation could decrease the depletion of neurons and oligodendrocytes. Inflammation modulation by suppressing polarization towards proinflammatory microglia, inhibiting the activation of A1 astrocytes, facilitating anti-inflammatory microglial activity and enhancing apoptotic cell clearance may provide beneficial neuroprotection for TBI. Exosomes are important carriers of intercellular communication. Both microglia and neural stem cell-derived exosomes mediate inflammatory injury and exert neuroprotective effects. Microglia-derived exosomes affect NSC proliferation and differentiation through encapsulated proteins and miRNAs after brain injury . ExosomeMarshall et al.  found thIt has been demonstrated that NSC transplantation can serve as a promising therapy for brain injury and especially exhibits proangiogenic and proregenerative effects . ExosomeThe cascade after TBI can cause apoptosis of nerve cells . A serieNSC exosome administration is an underlying strategy for suppressing apoptosis resulting from brain injury. Previous research has shown that neural stem cell-derived exosome administration can effectively reduce microglial density and neuronal apoptosis, thereby steadily improving functional recovery after middle cerebral artery occlusion . NumerouDue to their unique nanostructure, lack of immunogenicity , 100, loOne of the strategies for the preparation of engineered exosomes is cell engineering. Genetic engineering of parental cells is one of the commonly used cell engineering techniques, that is, directly modifying exosomes during exosome biogenesis. Alvarez-Erviti et al.  discoverThe utilization of well-characterized exosomes derived from NSCs under specific culture environments and NSC-derived exosomes engineered to carry the required miRNAs, mRNAs and proteins holds great promise in the treatment of brain injury. Neurons could be specifically targeted to receive a functional siRNA by systematically injecting engineered exosomes . Chen etSimilar to most exosomes, exosomes secreted by NSCs have the following advantages in the treatment of brain injury. First, exosomes are nanosized vesicles that can cross the BBB smoothly and are easily absorbed, with a very low likelihood of small vessel occlusion following intravenous injection , 119. SeExosomes secreted from NSCs have shown promise in the field of regenerative therapy, including the treatment of TBI. Despite the ever-increasing number and promising results of NSC-derived exosome studies in TBI therapy, translational research towards preclinical and clinical studies remains a long way off. There are still many barriers to overcome before they can be successfully implemented for TBI patients. As discussed in the review, these limitations include establishing a stable amplification system of NSC exosomes without heterologous components, the creation of uniform standards for purification and storage methods for the formation of NSC exosomes and, crucially, defining a method for single-exosome NSC analysis for a better understanding of the characteristics and mechanisms underlying exosome-based therapies.Exosomes have obvious heterogeneity. One crucial reason is that their small size and limited carrying capacity result in the differential distribution of specific proteins. Another reason is that gene expression changes induced by environmental factors such as circadian rhythm, stimulation, stress, infection and cell cycle may drive the occurrence of exosome heterogeneity. Therefore, a suitable and effective method for the purification of NSC exosomes should be employed to meet the requirements of current good manufacturing practices without changing the biological activity of exosomes, which can effectively provide a homogeneous NSC exosome population containing similar RNA, proteins and lipids. Regarding exosome purification methods, although a variety of purification methods have been established, there are biological differences in the exosomes obtained by each method. Ensuring high yield and high quality of exosomes is the key to exosome research. At present, there is still a lack of safe, effective and high-yield methods for the production and purification of exosomes, which limits the clinical transformation of exosomes for disease treatment. For exosome preservation methods, exosomes are routinely resuspended in PBS or 10% DMSO and stored at − 80 °C, which does not ensure exosome activity. Therefore, the purification and preservation method standards of NSC exosomes should be thoroughly discussed to ensure the acquisition of high-yield and high-quality exosomes and to promote the clinical transformation of NSC exosomes for TBI treatment. Moreover, our understanding of the biological functional diversity of NSC exosomes is still limited, and the mechanism of interaction between NSC exosomes and recipient cells to regulate target cells cannot be drawn in depth. Consequently, the release, transport route and fate of NSC exosomes are tracked at the level of single vesicles combined with imaging methods, and the basic functions of exosomes are further elucidated for the theoretical foundation for future clinical transformation.Despite the current challenges in the clinical translation of NSC exosomes, in addition to gene modification, NSC exosomes can also be combined with drug-carrying nanoparticles to realize the advantages of both and give NSC exosomes broader development prospects in the future.In summary, presently one of the most promising treatment approaches for brain injury is based on NSC exosome administration. Due to the beneficial effect on NSC exosomes after damage to nerves in the brain, it is necessary to explore the potential mechanisms in the regulation of neuroregeneration by NSC exosomes. The underlying mechanisms of exosomes derived from NSCs for brain injury are probably due to their neuroregeneration, anti-inflammatory, angiogenesis and anti-apoptosis properties Fig. . Further


The human race advanced in the last century in an exponentially growing increase of knowledge. We can send rockets to space, use computers that can easily store terabytes of information and do billions of instructions per second, develop artificial intelligence that is hard to distinguish from a living human person and build smartphones that can communicate dozens of megabytes of information every second between distant places on earth. However, despite major advances in the medical field, many brain-related disorders and diseases still have no cures today, and often we cannot even understand why the disease has started. Disease modeling should therefore be a top priority. Stem cell models and regeneration using stem cells play an important role and hold great promise both for understanding disease and also for cures, especially in neurodegenerative disease. In this Research Topic of Frontiers in Aging Neuroscience, important advances in the field have been reported. This Research Topic includes models for neurodegenerative diseases, potential new therapeutics, and related reviews summarizing what is currently known in the field.Limone et al. reviewed the literature on this important topic. The authors cover advances in methods used to differentiate human pluripotent stem cells into several highly specialized types of neurons, including cholinergic, dopaminergic, and motor neurons, and the potential clinical applications of stem cell-derived neurons for common neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, ataxia, and amyotrophic lateral sclerosis. Differentiation techniques for glial cell populations are also described in their review, including oligodendrocytes and microglia. Clinical trials of cell replacement therapies in the nervous system are underway holding great promise in regenerative medicine.Patient-derived neurons are excellent models but in addition, are now considered also as a huge potential for transplantation and cell replacement in the cases of neurodegeneration or trauma. Nam et al. have sought to explore the regenerative potential of an autologous bone marrow-derived mesenchymal stem cell (BM-MSC) product (Neuronata-R® lenzumestrocel) in amyotrophic lateral sclerosis (ALS). The survival rate of 157 patients treated with intrathecal lenzumestrocel was compared with placebo-treated patients. Remarkedly, the treated patients' survival after 500 and 1,000 days were orders of magnitude higher than the placebo groups, even with a single dose. Therefore, lenzumestrocel treatment is concluded to have a significant, long-term survival benefit in ALS patients.Mesenchymal stem cells have also been shown to incur regenerative possibilities  on the brain and its link to the activation of specific signaling pathways. The study provides compelling evidence of the molecular pathology underlying obesity-related brain damage and cognitive impairment. It highlights the importance of understanding the impact of HFD on brain metabolism, especially in the context of aging and neurodegenerative diseases. These findings contribute to the development of diagnostic strategies and personalized treatment approaches for age-related conditions and neurodegenerative disorders.Wang et al. have investigated Obstructive Sleep Apnea (OSA) that leads to hypoxia and sleep disturbance. The authors used structural equation modeling to investigate how hypoxia and sleep disturbance affect gray matter structures. For this, 74 participants underwent overnight polysomnography and T1-weighted Magnetic Resonance Imaging. The computational models revealed hypoxia-associated increases in gray matter volume, cortical thickness, and sulcal depth. Sleep disturbance on the other hand was shown to be largely associated with reduced gray matter volume and sulcal depth.Sleep disturbances have been previously associated with an increased probability of cognitive decline and neurodegeneration  dysfunctions that are mediated by the activation of two receptors, tropomyosin receptor kinase B (TrkB) receptor and the p75 neurotrophin receptor and are involved in physiological and pathological processes throughout life. Their review discusses the current knowledge and future directions in BDNF-associated research with an emphasis on the physiological and pathological functions in a long list of neurodegenerative diseases as well as other diseases such as diabetes and cancer. Methods to increase BDNF levels are discussed and BDNF-overexpressed stem cell transplantation is suggested as a possible promising therapeutic strategy.The dysfunction of BDNF signaling has central roles in neurological disorders including psychiatric and neurodegenerative diseases  on neuronal development. IUGR is known to cause neurodevelopmental abnormalities, and this model mimics the conditions seen in humans. The neuroprotective properties of lactoferrin, a potential therapeutic agent, were highlighted in preventing adverse effects on neurite length associated with IUGR. These findings provide valuable insights into the development of interventions to protect against IUGR-induced alterations in neuronal development and improve long-term cognitive outcomes.In the study of Lin et al. unravel the role of C-X-C motif chemokine 12 (CXCL12) in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). The team used gene therapy to upregulate CXCL12 in the spinal cord of rats and induced EAE. They found that upregulated CXCL12 alleviated EAE symptoms and reduced clinical scores. The levels of myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP) were higher in the CXCL12 group, indicating enhanced remyelination. Interestingly, the upregulation of CXCL12 did not induce significant leukocyte infiltration into the spinal cord. The study also demonstrated that CXCL12 promoted the differentiation of OPCs into oligodendrocytes in vitro. This study offers new avenues for targeting the CXCL12/CXCR4 axis as a potential therapeutic approach to enhance remyelination in MS and sheds light on the underlying mechanisms involved.Zhang et al. provides insights into the risk factors associated with prognosis. Female gender, younger age, higher contrast medium dose, and cerebral angiography procedure were linked to a poorer prognosis. Comorbidities such as hypertension, diabetes mellitus, renal insufficiency, and previous reactions to contrast media were also identified as potential risk factors. Neuroimaging and cerebrospinal fluid examination can aid in diagnosing CIE and distinguishing it from other neurological conditions. Supportive care, hydration, steroids, mannitol, and anti-epileptic medications are common treatment approaches. The review emphasizes that CIE can have lasting neurological effects, even with low doses of contrast media, and highlights the need for further research to better understand and manage this condition.Contrast-induced encephalopathy (CIE) is a rare complication arising from exposure to iodinated contrast media during angiographic procedures. The review from Huang et al. explore the use of CT-guided extracranial radiofrequency ablation for Meige's syndrome. They performed radiofrequency ablation on cranial nerves involved in the condition, targeting specific muscles. They found that the treatment resulted in symptom alleviation, although some patients experienced mild facial paralysis and sensory changes. Recurrences were observed in two cases. They suggested that CT-guided extracranial radiofrequency ablation could be a potential treatment option for Meige's syndrome, in addition to botulinum toxin injections and deep brain stimulation.Meige's syndrome is a rare form of cranial dystonia. Current treatments such as oral medications and botulinum toxin injections have limitations. Deep brain stimulation is an alternative but has technical requirements and high costs. Li M. et al. performed patch-clamp recordings of mitral cells (MCs) in the mouse olfactory bulb (OB) and found involvement of glutamate receptors in NH+ channel (Kv) that may be linked to an attenuation of the spontaneous firing amplitudes. NHA major complication of liver disease is Hepatic encephalopathy. Through elevated levels of ammonia/ammonium in the blood and cerebrospinal fluid, the patients suffer from olfactory dysfunction. SS: Conceptualization, Writing—original draft, Writing—review and editing. SL: Conceptualization, Writing—original draft, Writing—review and editing.


Cardiovascular disease and metabolic disorders are disproportionately prevalent among Hispanic and Latino adults in the United States. We extracted a posteriori dietary patterns (DPs) among a nationally representative sample of 2049 Hispanic adults using the 2013–2018 National Health and Nutrition Examination Survey. Three primary DPs and their tertiles were identified, and their associations with cardiometabolic outcomes were examined. Those with higher levels of the Solids Fats, Cheeses, Refined Carbohydrates DP were more likely younger, male, and Mexican American. Those with higher levels of the Vegetables DP were more likely female, higher income, and long-term immigrant residents. Those with higher levels of The Plant-Based DP tended to have higher education levels. Higher levels of the Solid Fats, Cheeses, Refined Carbohydrates DP level were positively associated with body mass index  and negatively associated with lower high-density lipoprotein cholesterol (HDL-C) levels . Higher levels of adherence to the Vegetables DP were negatively associated with body fat  but also HDL-C . The Plant-Based DP showed no associations with cardiometabolic outcomes. Future research and interventions should consider these associations as well as the sociodemographic differences within each DP. Cardiovascular disease (CVD) and metabolic disorders, collectively referred to as cardiometabolic outcomes, pose a significant health burden. Among the various populations affected, Hispanic and Latino adults in the United States have shown a disproportionate prevalence of these conditions, often characterized by a higher prevalence of obesity and diabetes. For example, Hispanic adults are more likely to have type 2 diabetes 17%) compared to non-Hispanic White adults (8%) [7% comparDiet plays a pivotal role in the development and progression of cardiometabolic diseases. Evidence suggests that dietary patterns, encompassing the overall composition and combination of foods consumed, may have a more comprehensive influence on health outcomes than individual nutrients or specific food items . HoweverThis manuscript aims to address this research gap by presenting a detailed investigation into the dietary patterns of Hispanic adults in the United States and their associations with cardiometabolic outcomes. By utilizing nationally representative data, this study seeks to provide a comprehensive analysis that captures the diversity within the Hispanic population while also accounting for the complex interplay between sociodemographic factors. The utilization of nationally representative data enables us to explore a wide array of dietary patterns among Hispanic adults, including variations based on nativity and duration, socioeconomic status, and other factors. We address the following research questions in this paper: (1) Which dietary patterns are the most prominent among a nationally representative sample of Hispanic adults in the United States? (2) What are the sociodemographic characteristics within tertiles of each of these dietary patterns? (3) Are the tertiles of these dietary patterns associated with cardiometabolic biomarkers and outcomes?We used data from the National Health and Nutritional Examination Survey (NHANES)  from 201We restricted our analytic sample to adults aged 18 and older and those who identified as “Mexican American” or “other Hispanic” when asked about their race and ethnicity (n = 4585). We further restricted inclusion to those participants who had completed two separate reliable 24-h dietary recalls (n = 2376). This decline in sample size was due to the lower proportion of Hispanic adults who had undergone two 24-h dietary recalls. Reliable dietary recalls must meet certain criteria as defined by the NHANES, which include assessing the quality and completeness of a survey participant’s response to the dietary recall section. Finally, we further restricted inclusion to those participants who had data for all demographic questions on age, sex, income, level of education, and nativity and duration of residence in the United States, resulting in a total sample size of 2049 participants. NHANES provides guidelines for creating sample and variance units for public-use data files, including sample weights for selected subsamples such as the fasting subsample. We used the appropriate sampling weights in our statistical analyses to provide reasonable, unbiased, and design-consistent estimates of variance ,12. BaseDietary intake was assessed in the NHANES study via two separate dietary recalls. All NHANES participants are eligible for two 24-h dietary recalls. The first dietary recall is collected in person at the MEC, and the second recall, which only a subset of participants complete, is collected via telephone 3 to 10 days later. Both recalls are offered in English and Spanish as well as other languages ; then, iFor this study, we identified and used mutually exclusive food groups (28 FPED components). We excluded food groups that in total or in aggregate consisted of two or more food groups. The excluded duplicative, total, or aggregate groups were beans and peas (computed as protein foods); total fruits; total vegetables; total red and orange vegetables; total starchy vegetables; total grains; total protein foods; total meat, poultry, and seafood; and total dairy. The 28 FPED components used in this study were citrus, melons, and berries; other fruits; fruit juice; dark-green vegetables; tomatoes; other red and orange vegetables; potatoes; other starchy vegetables; other vegetables; beans and peas (computed as vegetables); whole grains; refined grains; meat; cured meat; organ meat; poultry; seafood high in omega-3 fatty acids; seafood low in omega-3 fatty acids; eggs; soy products; nuts and seeds; milk; yogurt; cheese; oils; solid fats; added sugars; and alcoholic drinks.We then used exploratory factor analysis, a data reduction technique, to identify unique dietary patterns within the 28 food groups . This meWe then used principal component analysis (PCA) to identify unique dietary factors from the 28 food groups. We conducted orthogonal rotation with the varimax option to derive non-correlated factors and minimize the number of indicators  that had high loading on one factor ,19. The predict command in Stata. These scores were subsequently utilized for both data exploration and prediction models [Once we selected which factors to retain, we computed predicted scores of every retained factor for each respondent using the n models . These pOur dependent variables consisted of laboratory, clinical, and self-report measures related to cardiometabolic health that are available in the NHANES. We examined body mass index, type 2 diabetes , glycohemoglobin levels, body fat percentage obtained via dual-energy x-ray absorptiometry (DXA), self-reported history of myocardial infarction , self-reported history of coronary heart disease , high-density lipoprotein cholesterol levels (mg/dL), fasted low-density lipoprotein Cholesterol levels (mg/dL), fasted triglycerides (mg/dL), systolic blood pressure (mmHg), and diastolic blood pressure (mmHg). Additional information about these measures can be obtained on the NHANES website .Covariates for all models included age (years); sex ; education level ; income ; and caloric intake . These demographic variables are highly correlated with dietary intake and cardiometabolic outcomes. We controlled for caloric intake as we wanted to test the associations between dietary patterns and cardiometabolic outcomes independent of energy. For type 2 diabetes and glycohemoglobin, we also controlled for whether participants were on a special diet tailored for diabetes (yes/no), currently taking insulin (yes/no), or currently taking medication to control blood sugar levels (yes/no). For history of coronary heart disease and myocardial infarction, we also controlled for smoking. For high-density-lipoprotein cholesterol, we also controlled for physical activity levels (METS minutes per week). For triglycerides, we also controlled for glycohemoglobin levels. For both systolic and diastolic blood pressure levels, we also controlled for smoking.We examined the association between the tertiles of the dietary patterns and cardiometabolic outcomes. While our aforementioned selection criteria identified 11 unique factors, we only retained three different dietary patterns as outcomes in the regression models, as the first three factors explained the most variance and had the most interpretable dietary patterns. We regressed scores for each of the three unique dietary patterns on our cardiometabolic outcomes using linear regression for continuous variables and logistic regression for binary variables. We included the following covariates in all regression models: age, sex, education, income, and caloric intake. We conducted sensitivity analyses by including additional covariates  through a stepwise regression approach in all models, but not all models were impacted by the addition of these covariates. All statistical analyses were conducted using Stata 16 IC, StataCorp LLC, College Station, TX, USA, .p < 0.001), indicating homogeneity of variance through the consumption of foods. Eleven components, or factors, were extracted via factor analysis for different food groups using the criteria stated above. The 11 factors had an eigenvalue over 1, accounting for 58.4% of the total observed variation in the food-consumption patterns among Hispanics . The results of the Bartlett test of sphericity were highly significant  were observed for solid fats, refined grains, cheese, added sugars, and tomatoes and tomato products. The second factor, which accounted for 8.7% of the total variance, was labeled as the Vegetables dietary pattern, as high factor loadings were observed for red and orange vegetables, tomato and tomato products, dark-green vegetables, and other vegetables. The third factor, which accounted for 5.2% of the total variance, was labeled as the We examined the sample characteristics for each of the three dietary patterns and found significant differences across the tertiles of each dietary pattern score corresponding to specific demographic and socioeconomic variables . For theFor the Vegetables dietary pattern , there wFor the Plant-Based dietary pattern , the onlThe results of the regression models are depicted in For the Vegetables dietary pattern, there were statistically significant associations with body fat percentage and HDL-C. Persons in the second and highest tertiles had lower body fat levels than those in the lowest tertile, with those in the highest tertile having statistically significant lower levels of body fat. Persons in the second tertile had a statistically significant lower HDL-C value than those in the lowest tertile. However, while not statistically significant, persons in the highest tertile had a higher HDL-C value than those in the lowest tertile. There were no statistically significant associations between the Vegetables dietary pattern and other cardiometabolic outcomes.There were no statistically significant associations between the Plant-Based dietary pattern and cardiometabolic outcomes.We extracted and identified three unique dietary patterns that were the most common among a nationally representative sample of Hispanic adults. We then examined the sociodemographic characteristics within the tertiles of each dietary pattern as well as the association between the tertiles of the dietary patterns and eleven cardiometabolic outcomes. We found that higher levels of adherence to the Solid Fats, Cheeses, and Refined Carbohydrates dietary pattern were positively associated with body mass index and negatively associated with high-density lipoprotein cholesterol. Higher levels of adherence to the Vegetables dietary pattern were negatively associated with body fat percentage but also with high-density lipoprotein cholesterol. We found no associations between the Plant-Based dietary pattern and cardiometabolic outcomes.This study’s results reveal significant associations between dietary patterns and various demographic and socioeconomic factors, providing a deeper understanding of the complex relationship between diet and cardiometabolic health among a nationally representative sample of Hispanic adults living in the United States.For the Solid Fats, Cheese, and Refined Carbohydrates dietary pattern, it is noteworthy that individuals with higher scores tended to be younger, male, and more likely to be of Mexican American origin. These findings suggest that younger Hispanic adults, particularly males of Mexican American descent, are more prone to consuming diets characterized by high amounts of solid fat, cheese, and refined carbohydrates. This demographic variation highlights the importance of targeted interventions for specific subgroups within the Hispanic population.Conversely, the Vegetables dietary pattern was associated with differences in sex, income, and nativity/duration of residence. Women were more likely to adhere to this pattern, as were individuals with higher household incomes, indicating that women and those with a high-income status prioritize vegetable consumption in their diets. Additionally, immigrants living in the US for 10 years or more were more likely to follow this pattern compared to US-born Hispanics, potentially demonstrating protective factors attributed to this population that may be related to health selection characteristics  as well as selective emigration   and lessThe Plant-Based dietary pattern was associated with higher levels of education, with individuals who had attained higher education being more likely to follow this pattern. This finding aligns with previous research that has shown a positive correlation between educational attainment and the adoption of plant-based diets, reflecting a greater awareness of the health benefits associated with these dietary choices ,29.The regression models provided insights into the associations between dietary patterns and cardiometabolic outcomes among Hispanic adults. For the Solid Fats, Cheese, and Refined Carbohydrates dietary pattern, higher adherence was associated with higher body mass index (BMI) values and lower levels of high-density lipoprotein cholesterol (HDL-C). These results are consistent with the established understanding that diets rich in solid fats and refined carbohydrates contribute to obesity and unfavorable lipid profiles . These aIn contrast, the Vegetables dietary pattern was associated with lower body fat percentages, constituting a positive health outcome, indicating that individuals adhering to this pattern tend to have healthier body compositions. However, it is important to note that there was a statistically significant lower HDL-C value among individuals in the second tertile of adherence, although those in the highest tertile exhibited a higher, albeit non-statistically significant, HDL-C value compared to those in the lowest tertile. These findings suggest a complex relationship between vegetable consumption and HDL-C levels that warrants further investigation.Surprisingly, the Plant-Based dietary pattern did not demonstrate statistically significant associations with any of the cardiometabolic outcomes assessed in this study. This result could be attributed to the diverse nature of this dietary pattern, as it encompassed a wide range of foods with varying nutrient compositions, including red vegetables, soy, nuts and seeds, and fruits. The individual choices within this dietary pattern may have different effects on health, and further research is needed to explore these variations.This study had both limitations and strengths. Using the nationwide NHANES data from 2013–2018 was a strength because it included a large, diverse sample of Hispanic adults. In addition, the use of a posteriori derived dietary patterns, rather than a priori indices, was a strength, as they highlight actual dietary patterns that a representative sample of Hispanic adults, in aggregate, adhered to in the United States from 2013 to 2018. Another strength is our use of the average of dietary recalls rather than relying on just one 24-h dietary recall, with the latter being less likely to reflect usual intake. Key limitations of this study include the cross-sectional nature of the data and study design, which prevented us from inferring causality or directionality. Additionally, we reported our logistic regression results utilizing adjusted odds ratios for three dichotomous outcomes . Odds ratios might have led to overestimation of the associations among these outcomes since we utilized cross-sectional data in our study and thus introduced potential bias. However, none of these associations were statistically significant. We chose to utilize odds ratios, rather than prevalence ratios or predicted probabilities, in order to increase the interpretability of comparing the associations within (tertiles) and between dietary patterns among the 11 cardiometabolic outcomes. An additional limitation is that the dietary data and some of the cardiometabolic measures relied on self-report data, including respondents’ history of coronary heart disease and myocardial infarction. Self-report measures are subject to both recall and social desirability biases ,31. If sThe findings from this study offer valuable insights into dietary patterns and their associations with cardiometabolic outcomes among a nationally representative sample of Hispanic adults. They emphasize the importance of considering demographic, socioeconomic, and cultural factors when designing interventions and public health strategies intended to improve cardiometabolic health within this population. Targeted interventions should be developed to address specific dietary patterns associated with unfavorable cardiometabolic outcomes, such as the Solid Fats, Cheese, and Refined Carbohydrates dietary pattern. These interventions should be tailored to the unique needs of subgroups within the Hispanic population, taking into account age, gender, ethnicity, income, and acculturation status. For example, we found that younger Hispanic adults, particularly males of Mexican American descent, are more prone to consuming diets characterized by high levels of solid fat, cheese, and refined carbohydrates. This highlights the importance of targeting and tailoring interventions for specific demographic subgroups within the broader Hispanic population.Future researchers should explore the mechanisms underlying these associations, investigate the impact of specific dietary components on metabolic pathways, and conduct longitudinal studies to establish causality. Additionally, comparing dietary patterns and their associations with cardiometabolic outcomes between various groups in the United States will help provide more insight into personalized nutrition. Future studies examining dietary patterns and cardiometabolic outcomes among Hispanics and Latinos should examine differences by subgroup as there is much diversity within these aggregated groups. Additionally, qualitative research methods could be employed to gain deeper insights into the cultural and social factors, as well as the preferences and traditions, that influence dietary choices among Hispanic adults.In conclusion, this study’s results provide critical information for policymakers, healthcare providers, and researchers seeking to address health disparities and promote cardiometabolic health among Hispanic communities in the United States. By understanding the complex interplay between dietary patterns, sociodemographic factors, and health outcomes, we can develop more effective strategies to reduce the burden of cardiometabolic diseases within this population and advance health equity.


To date, studies investigating radiomics-based predictive models have tended to err on the side of data-driven or exploratory analysis of many thousands of extracted features. In particular, spatial assessments of texture have proven to be especially adept at assessing for features of intratumoral heterogeneity in oncologic imaging, which likewise may correspond with tumor biology and behavior. These spatial assessments can be generally classified as spatial filters, which detect areas of rapid change within the grayscale in order to enhance edges and/or textures within an image, or neighborhood-based methods, which quantify gray-level differences of neighboring pixels/voxels within a set distance. Given the high dimensionality of radiomics datasets, data dimensionality reduction methods have been proposed in an attempt to optimize model performance in machine learning studies; however, it should be noted that these approaches should only be applied to training data in order to avoid information leakage and model overfitting. While area under the curve of the receiver operating characteristic is perhaps the most commonly reported assessment of model performance, it is prone to overestimation when output classifications are unbalanced. In such cases, confusion matrices may be additionally reported, whereby diagnostic cut points for model predicted probability may hold more clinical significance to clinical colleagues with respect to related forms of diagnostic testing. WhilSpatial filters are image processing methods that enhance spatial image properties of a region of interest such as edges and/or textures –25. The Directional gradients and direction invariant gradients have been used to improve edge enhancement. For example, edge filters such as Kirsch and Sobel have been reported as part of multiple radiomics panels , 29. LikIn some cases, noise can be suppressed using image transforms, such as Fourier analysis . In thisStatistical characterizations of texture can also be assessed from higher-order texture methods  such as Gray-Level Co-Occurrence Matrix (GLCM), Gray-Level Run-Length Matrix (GLRLM), Gray-Level Size-Zone Matrix (GLSZM), Gray-Level Dependence Matrix (GLDM) and Neighborhood Gray-Tone Difference Matrix (NGTDM) , 36. In In contrast to GLCM, GLRLM quantifies the pattern of gray-level intensity pixels in a fixed direction from an interference pixel . Some coSimilar to GLCM, in GLSZM texture is also quantified based on how often a combination of gray-level values occurs next to each other at a given distance within a region of interest , 37; howLikewise, GLDM quantifies the number of connected voxels within a set distance that are dependent on a center voxel . A neighLastly, NGTDM evaluates the difference between a particular gray-level intensity and the average gray-level intensity of its neighborhood within a given distance , 37, 42.Structural methods involve techniques of decomposing an image into basic units and then identifying the rules required to construct that given image from its basic units. For instance, Fractal Dimension (FD) is a metric that evaluates image complexity by quantifying how changes in image scale affect image detail , 43, 44.In oncologic imaging, radiomics analysis has shown great utility in evaluating features of intratumoral heterogeneity, which may correspondingly reflect tumor behavior , 47, 48.Given the sheer number of radiomics features extracted as part of standard pipeline workflows, analyses of radiomics datasets are often necessarily complex and difficult to comprehend. Moreover, segmentation approaches  can likewise affect the extracted radiomics parameters and—particularly in the case of manual segmentation—be a source of intra- and inter-observer variability , 52. Inir > 0.8 suggesting collinearity) should be performed as the initial approach for dimensionality reduction , and elimination of highly correlated features . Howevereduction .Reporting of machine learning performance for radiomics based models is commonly done using area under the curve (AUC) of the receiver operating characteristic (ROC). In general, while AUC can well-represent overall model prediction accuracies, it is prone to overestimating performance in cases of unbalanced classification outputs. To overcome this, a common approach is to report confusion matrices—including sensitivity , specificity (selectivity), positive predictive value (precision), and negative predictive value—corresponding to various cut points for model predicted probability. These values likewise tend to be more easily understood by clinical colleagues, whereby diagnostic cut points in some ways hold more tangible clinical significance with respect to other forms of diagnostic testing. To obtain optimal cut points, common practice includes statistical approaches such as Youden's J statistic , defined as J = sensitivity + specificity—1, or simply selecting the cut points that maximize the product of sensitivity and specificity , 62. An Machine learning analyses of radiomics feature sets have been applied to a wide array of classification and prognostication tasks in oncologic imaging. Spatial assessments in particular have shown great potential to quantitatively evaluate features of intratumoral heterogeneity and may one day prove to be important prognostic biomarkers of phenotypic behavior in oncologic care. In this review, we discussed some of the most common approaches to spatial assessment of texture in radiologic imaging as well as familiar reporting metrics to assess model performance in machine learning studies.