Age-related disorders known as neurodegenerative illnesses are defined by uncontrolled neuronal loss that gradually impairs brain function. The majority of age-related neurodegenerative disorders are caused by dementias, in particular. Nowadays, the neurodegenerative disorders are not limited to age and are reported in all age groups. The drug delivery to treat the neurodegenerative disorders is challenging due to the presence of the blood-brain barrier (BBB). A critical literature review has been conducted across databases such as Scopus, Embase, Cochrane, and PubMed. Blood-brain barrier, neurodegenerative disorders, novel drug delivery system, and targeted drug therapy were the search terms. Neurodegenerative Diseases (NDD) impact the peripheral nervous system, nerve cells, muscles, and the nerve-muscle junction. This term broadly encompasses cognitive disorders, such as Alzheimer's disease, Lewy body dementia, frontotemporal dementia, and vascular dementia. Additionally, other neurodegenerative conditions such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, and spinocerebellar ataxias predominantly impair motor system function and nerves in the limbs. The existing therapeutic approaches to treat neurological diseases exhibit limited efficacy due to the BBB. This highly selective semipermeable membrane permits vital nutrients to enter the brain while blocking the potentially harmful toxins. It makes it very challenging to get medications into the brain. There are several effective approaches to deliver drugs to the brain (nanocarrier systems, intranasal administration, and focused ultrasound) to address the limitations of conventional treatments. This review discusses neurodegenerative disorders, brain anatomy/physiology, barriers to drug delivery, and strategies to overcome these limitations.
Advancements in drug delivery systems (DDSs) have revolutionized pharmaceutical development by enhancing therapeutic precision, minimizing off-target effects, and improving patient compliance. Modern DDS technologies, such as lipid nanoparticles (LNPs), liquid-liquid phase separated (LLPS) systems, inorganic nanoparticles, GalNac systems, small molecules, dendrimers, polymers, peptides, and silk fibroin (SF) hydrogels, have significantly expanded the range of anti-cancer therapeutics. These advancements extend beyond conventional chemotherapeutics to include biologics such as nucleic acids (NAs), peptides, proteins, and monoclonal antibodies. These innovations have transformed oncology treatment paradigms and are gradually being adapted for central nervous system (CNS) disorders, where effective drug delivery is hindered by the protective blood-brain barrier (BBB) and the intricate architecture of neural networks. In this context, stimuli-responsive DDSs have emerged as promising tools, capable of crossing the BBB and releasing drugs in response to pathological cues. Theranostic DDSs, which integrate diagnostic and therapeutic functionalities into a single platform, hold particular promise in imaging-guided interventions. This review provides a comprehensive overview of DDS applications in both oncology and neurodegenerative diseases (NDDs), emphasizing mechanistic insights, delivery strategies, and material innovations. Furthermore, it explores key translational considerations - including safety, efficacy, and clinical scalability - essential for advancing next-generation DDS platforms from bench to bedside, thereby maximizing therapeutic outcomes in complex diseases.
To investigate whether antidiabetic drugs have a biological basis to be repurposed in PD prevention, we applied a drug target Mendelian randomization framework to assess associations between genetic variation in antidiabetic drug targets and PD risk or age at onset (AAO). Instrumental variables (IVs) were derived from GWAS summary statistics on fasting glucose (FG), glycated hemoglobin (HbA1c), and gene expression data from GTEx. Apart from SGLT2 inhibitors, all other antidiabetic drugs of interest could be instrumented through our methods. Positive and negative control analyses were carried out to validate 20 IVs in the FG arm and 23 IVs in the HbA1c arm. DPP-4 inhibitors failed the positive control. GWAS summary statistics for PD risk and AAO data were sourced from the IPDGC and COURAGE-PD consortia, resulting in 42 083 cases/457 090 controls for risk and 37 103 PD cases for AAO. MR analyses showed no significant associations across consortia or in meta-analysis. These findings do not support a causal role of genetic variation in antidiabetic drug targets in PD risk or AAO.
Therapeutic drugs for central nervous system (CNS) diseases need to reach CNS tissues. However, the blood-brain barrier often limits their therapeutic effects. To address this issue, highly invasive drug administration routes, such as intracerebroventricular or intrathecal administration, can be used. In addition, intranasal (i.n.) administration is increasingly being recognized as a non-invasive route, although its application in humans is limited. Hence, we explored intratympanic (i.t.) administration as a novel, minimally invasive route for direct drug delivery to the CNS. The aim of this study was to develop a new administration route that enables efficient and comprehensive evaluation of CNS drug transport by employing cassette dosing. Using this approach, we assessed multiple low- and high-permeability drugs concurrently in rodents and non-human primates. Pharmacokinetics were evaluated in cerebrospinal fluid (CSF) and brain tissues to investigate the potential for enhanced CNS penetration. Furthermore, the effects of cetirizine, a second-generation histamine receptor antagonist, on spontaneous locomotor activity were examined following i.t. and intravenous (i.v.) administration. I.t. of low-permeable drugs such as cetirizine markedly increased their penetration into CSF and brain in both rats and monkeys. Pharmacologically, i.t. of cetirizine significantly decreased spontaneous locomotor activity in rats, whereas such effects were not observed following i.v.. This study demonstrates that i.t. may serve as a promising route (Ear-to-Brain) for treating neurodegenerative diseases that currently lack effective treatment options.
Central nervous system (CNS) disorders, particularly neurodegenerative diseases and brain tumors, pose substantial and long-standing challenges to the global public health system. Current therapeutic approaches for CNS disorders are primarily confined to symptomatic relief and generally fail to halt or reverse disease progression. However, proteolysis-targeting chimeras (PROTACs), as an emerging therapeutic strategy, have introduced new prospects for effective intervention in this domain. Although several studies have demonstrated the use of PROTACs in degrading pathogenic proteins associated with CNS disorders, their clinical translation remains hindered by multiple challenges, including insufficient degradation efficiency, potential off-target toxicity, and limited blood-brain barrier (BBB) permeability. In response to the above challenges, researchers are actively pursuing various strategies-ranging from structural optimization of PROTACs to enhance their degradative activity, to the implementation of novel nano-delivery systems and targeted delivery approaches to improve BBB permeability and tissue selectivity. These strategic advancements have demonstrated significant potential in preclinical research for the treatment of CNS disorders. This review provides a comprehensive overview of the research and development of various PROTACs targeting CNS disorders, and highlights potential application strategies for advancing protein degrader therapeutics in the CNS field. By synthesizing current advances and challenges, it offers researchers in related disciplines a well-defined theoretical framework and forward-looking strategic guidance, thereby facilitating in-depth investigation and transformative applications in this rapidly evolving domain.
Diabetes mellitus has been linked to cognitive impairment and Alzheimer's disease (AD). They share common pathologic pathways, including insulin resistance, mitochondrial dysfunction, oxidative stress, and chronic neuroinflammation. These shared mechanisms have prompted interest in repurposing antidiabetic agents as promising therapies for neurodegenerative diseases. Despite this overlap, these drugs face translational challenges, primarily due to their poor penetration across the blood-brain barrier (BBB) and, consequently, poor central nervous system (CNS) bioavailability. Nanoparticle-based drug delivery offers an alternative route to improve targeting of the CNS by increasing the drug stability and augmenting transport across the BBB. Although preclinical evidence showed promising results, the extent to which these findings translate into clinically tangible outcomes remains uncertain. This review critically evaluates the main preclinical studies on nanoparticle-mediated delivery of antidiabetic agents, with particular emphasis on AD and diabetes-associated cognitive impairment, where most available data are concentrated. We also discuss the main brain-targeting strategies, their limitations, and the translational challenges to their clinical application, particularly for conditions beyond AD, where the evidence remains sparse. Addressing these barriers is crucial for the development of nanomedicine-based approaches from bench to bedside. This review provides a critical standpoint on the field and highlights priorities for future research aimed at the effective translation of nanoparticle-enabled therapies for neurodegenerative diseases.
Central nervous system (CNS) disorders pose a major global health challenge, yet therapeutic development is impeded by the difficulty of delivering effective drug concentrations to the brain. Based on a literature search of PubMed, Scopus, and Google Scholar (1990-2025), this review delineates the current landscape of computational modeling techniques addressing CNS drug delivery, emphasizing anatomical barriers and physiological transport mechanisms relevant to major neurological diseases. We categorize approaches spanning the molecular dynamics interactions of drug-blood-brain barrier (BBB) to macroscopic continuum and physiologically based pharmacokinetic (PBPK) models that elucidate systemic distribution and brain exposure. These models are assessed across established delivery routes, such as intranasal and intrathecal administration, and emerging methods, including focused ultrasound-mediated BBB opening and targeted nanoparticle delivery. We highlight the growing importance of integrating complex physiological phenomena, such as glymphatic flow and cerebrospinal fluid (CSF) dynamics, into predictive models. Finally, we explore opportunities involving multiscale digital twins of the CNS that integrate molecular interactions, vascular hemodynamics, perivascular flow, and parenchymal transport within patient-specific geometries. We also examine the role of machine learning and surrogate modeling in accelerating prediction of drug transport parameters and optimizing delivery strategies, aiming to guide the design of robust computational platforms.
Central nervous system (CNS) disorders remain one of the most significant challenges in medicine given the restrictive properties of the blood-brain barrier (BBB), which substantially reduces the delivery of most therapeutics to penetrate the brain. Although there has been considerable progress in the generation of support neuroactive substances, approximately 98% of possible CNS medicines never get to effective milligram proofs in the brain, mostly due to exclusion from BBB. This research offers an in-depth and analytical assessment of approaches utilizing nanomedicine aimed at addressing the limitations of the blood-brain barrier (BBB) and improving the delivery of drugs to the brain. It thoroughly explores the structural and functional properties of the BBB, identifies the major obstacles hindering molecular movement, and investigates the cellular and molecular processes that regulate the movement of nanoparticles. Significant focus is given to various nanocarrier platforms, encompassing lipid-based systems (such as liposomes, solid lipid nanoparticles, and nanostructured lipid carriers), polymeric nanoparticles, micelles, dendrimers, nanogels, nanoemulsions, exosomes, carbon nanotubes, and metallic nanoparticles. These platforms are particularly noted for their important functions in improving drug stability, bioavailability, controlled release, and precision targeting within the central nervous system. Furthermore, recent developments in innovative technologies, including nanofiber scaffolds and multidimensional (3D-6D) printing methods for neurological uses, are also discussed. The paper also analyses translational hurdles, safety issues, and toxicity factors that persistently obstruct the clinical application of nanomedicine-based CNS therapeutics. This paper highlights the revolutionary potential of nanotechnology in brain drug delivery and offers insights into future strategies for the rational design of safe and effective nanocarriers to meet unmet demands in CNS disease therapy.
The blood-brain barrier (BBB) is a major obstacle to targeted drug delivery for central nervous system (CNS) diseases. Although liposomes and polymeric nanoparticles have improved brain drug delivery, limitations remain in BBB targeting, long-term biocompatibility, and in vivo clearance. Exosomes are endogenous nanoscale extracellular vesicles with favourable biocompatibility, low immunogenicity, and BBB-crossing potential. Therefore, this bibliometric study summarises the current research status, future research trends, and challenges in the more specific field of exosome-mediated BBB drug delivery. A comprehensive search was conducted across the Web of Science Core Collection (WoSCC), PubMed, and Embase databases for relevant English-language literature on exosome-mediated drug delivery across the blood-brain barrier from 2015 to 2025. WoSCC served as the primary source for bibliometric analysis. PubMed and Embase databases were used for supplementary validation. Software such as VOSviewer, CiteSpace, and R-bibliometrix was employed for literature visualisation analysis. This study included 1,365 relevant articles from the WoSCC database, and the annual publication volume showed a steady upward trend. China and the United States significantly lead in both the number of publications and the number of core contributing institutions in this field. Co-occurrence analysis of keywords showed that research hotspots are mainly focused on exosomes, the blood-brain barrier, drug delivery, and Alzheimer's disease. PubMed and Embase were used as supplementary validation databases, including 1,089 and 1,517 records, respectively. Their annual publication trends, major countries/regions, core journals, and keywords/themes were generally consistent with WoSCC, supporting the macro-level stability of the bibliometric findings. Unlike previous bibliometric analyses that mainly focused on overall trends in CNS exosome research, this study focuses specifically on the direction of exosome-mediated drug delivery across the BBB. The findings show a shift from basic vesicle characterisation toward engineered delivery systems, CNS disease applications, and translational evaluation. Mammalian-derived exosomes remain dominant, while plant-derived vesicles, AI-assisted design, biomimetic hybrid nanovesicles, and gut-brain axis strategies are emerging areas of focus. Future research should prioritise systematic platform comparisons, standardised evaluation, quality control, scalable production, long-term safety, and regulatory pathways.
Neurological diseases with a complex etiology and diagnostic complexities are one of the major causes of disability and death globally. In previous preclinical studies, it has been shown that parthenolide (PTL) can provide significant neuroprotective potential. The review synthesizes the mechanistic data on PTL that explains the routes to therapy and creates a strong theoretical framework for future research and drug development. This review has done a literature search in databases of PubMed, Web of Science, China Science Periodical Database, and China National Knowledge Infrastructure for preclinical studies on PTL. The search terms used were "Parthenolide" and "Nervous System Diseases" as well as specific names of the diseases. We reviewed the mechanistic understanding on PTL of the available literature. PTL inhibits the pathogenesis and development of neurological disease via a wide variety of mechanisms, such as an anti-inflammatory effect, an anti-oxidative stress effect, a reduction of neuronal apoptosis, and the relief of neuropathic pain. Since it addresses more than one pathway in the multifactorial pathological network of neurological illnesses, PTL may have synergistic or additive therapeutic benefits. Multi-target therapeutic effects of PTL are effective in combating the interrelated pathological conditions of neurological disorders, whereas derivatives developed according to the structure-activity relationship (SAR) of PTL have additional potential to be clinically translated. Nevertheless, the existing data come mostly in the form of preclinical models, and their translation into clinical practice remains to be confirmed. PTL is a therapeutic agent with great promise in treating neurological disorders. Nevertheless, its potential as a translational drug also requires additional study and confirmation.
Background: Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp) central nervous system (CNS) infections represent a major therapeutic challenge in neurosurgical patients. Intraventricular or intrathecal polymyxin B sulfate (PMB) is commonly used as salvage therapy but is limited by substantial neurotoxicity. Ceftazidime-avibactam (CZA) exhibits potent in vitro activity against KPC-Kp; however, prospective clinical and pharmacokinetic evidence supporting its use in CNS infections remains limited. Methods: In this prospective, single-centre observational study, adult neurosurgical patients with culture-confirmed KPC-Kp CNS infections admitted to the neurointensive care unit of Huashan Hospital were enrolled. Patients received either intravenous CZA (CZA group, n = 15) or intrathecal/intraventricular PMB-based therapy (PMB group, n = 10). Primary outcomes included clinical cure, microbiological eradication, 28-day mortality, and safety. Therapeutic drug monitoring was performed to determine steady-state plasma and cerebrospinal fluid (CSF) concentrations of ceftazidime, avibactam, and polymyxin B, enabling assessment of CSF penetration and exposure-toxicity relationships. Results: Overall clinical cure and microbiological eradication rates were 68.0% and 84.0%, respectively, with a 28-day mortality of 20.0%. Compared with PMB, CZA was associated with a significantly higher clinical cure rate (86.7% vs. 40.0%, p = 0.024) and a numerically higher eradication rate (93.3% vs. 70.0%). No neurological adverse events occurred in the CZA group, whereas neurological toxicity was observed in 60.0% of PMB-treated patients (p < 0.001). Functional outcomes favoured the CZA group, with lower modified Rankin Scale scores at discharge and at 6 months. Pharmacokinetic analyses demonstrated that steady-state CSF concentrations of ceftazidime and avibactam exceeded commonly accepted pharmacodynamic targets, while markedly elevated PMB CSF concentrations were observed in patients with neurological toxicity. Conclusions: While intravenous CZA showed potentially favourable efficacy and safety compared with local PMB in this cohort, these preliminary findings should be interpreted as hypothesis-generating given the small sample size and non-randomised design. These results provide a rationale for further validation in larger multicentre, randomised controlled trials.
Tuberculosis (TB) is the leading global cause of death from a single infectious agent. Recent reductions in global health funding have threatened TB control, making comprehensive assessment of TB, HIV-related TB, and drug-resistant TB burdens before these disruptions essential for shaping effective responses. The WHO End TB Strategy sets targets of a 95% reduction in TB deaths and a 90% reduction in TB incidence between 2015 and 2035. Using results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023, this study aims to assess the burden of TB and multidrug-resistant TB (MDR-TB) across 204 countries and territories, and to evaluate progress towards the WHO End TB incidence and mortality targets. We quantified TB mortality using the Cause of Death Ensemble modelling platform with global vital registration, surveillance, verbal autopsy, and minimally invasive tissue sampling data. For TB morbidity estimation, we simultaneously modelled incidence, prevalence, and mortality by age and sex using DisMod-MR 2.1. A population attributable fraction (PAF) approach was applied to stratify morbidity and mortality estimates by HIV and drug-resistance status. We also calculated disability-adjusted life-years (DALYs) as the sum of years of life lost and years lived with disability. For the risk factor analysis, a comparative risk assessment framework was used and PAFs were derived for alcohol use, smoking, and high fasting plasma glucose to determine the proportion of TB burden associated with these risk factors. In 2023, there were an estimated 9·11 million (95% uncertainty interval 8·04-10·3) incident cases of all-form TB, 1·22 million (0·98-1·49) deaths, and 54·6 million (43·8-65·5) DALYs globally. HIV-related TB comprised 781 000 (690 000-879 000) incident cases and 210 000 (142 000-279 000) deaths, contributing 11·0 million (7·56-14·3) DALYs. MDR-TB accounted for 466 000 (198 000-1 080 000) incident cases, 102 000 (31 700-238 000) deaths, and 3·96 million (1·31-9·01) DALYs. From 2015 to 2023, global all-form TB incidence rates declined by 19·2% (17·8-20·5) and deaths declined by 22·6% (4·7-35·7); declines were larger for drug-susceptible TB than for MDR-TB. Sub-Saharan Africa and south Asia had the highest mortality burdens in 2023; reductions in all-form TB incidence and mortality were uneven between 2000 and 2023, with limited progress in both measures in Latin America and the Caribbean. Removing smoking, alcohol use, and high fasting plasma glucose would reduce global TB deaths to 768 000 (592 000-970 000) and DALYs to 34·9 million (27·8-43·8) in 2023; MDR-TB deaths would decrease to 77 200 (23 400-183 000) and DALYs to 3·12 million (1·03-7·29). Global progress towards WHO End TB targets is disparate and fragile. Although many regions achieved meaningful gains, others have stagnated in recent years. The complexity of TB prevention is amplified by divergent MDR-TB trends, the persistent burden of HIV, and growing exposure to modifiable risk factors. Recent volatility in global health financing threatens to further destabilise this vulnerable epidemiological landscape; concerted action is urgently needed to temper disruptions and preserve progress. Gates Foundation.
Migraine is a chronic neurological disorder that can significantly interfere with day-to-day functioning. Currently, migraine is treated with various drugs administered via oral or parenteral routes; however, conventional drug delivery methods have several limitations. The blood-brain barrier (BBB) poses a major obstacle for effective drug delivery to the central nervous system. To overcome these drawbacks, the intranasal (IN) route has emerged as a preferred alternative. Intranasal delivery offers a promising approach for targeting drugs to the brain, bypassing the limitations of oral and parenteral administration. However, this route also presents challenges, such as limited nasal volume, particle size restrictions, and molecular weight constraints of drugs. Notably, nanoparticle-based technologies have shown significant potential in overcoming these challenges, enhancing drug accumulation in the brain while minimizing systemic distribution. This review article was compiled through a thorough survey of recent research and review articles focused on CNS-targeted drug delivery via the nasal route. The literature search was conducted using databases and sources including PubMed, Scopus, Google Scholar, WHO publications, and relevant books. Keywords used for the search included: Neurological disorders, Migraine, Novel approaches, Nose-to-brain delivery, Challenges, and Nanoformulations. The reviewed studies demonstrate that various nanoformulations significantly enhance the brain delivery of anti-migraine drugs via the intranasal route. These delivery systems improve drug bioavailability, provide a faster onset of action, and achieve better therapeutic outcomes compared to conventional administration methods. Intranasal nanoformulations represent a promising strategy to overcome the limitations associated with conventional oral and parenteral migraine therapies by facilitating direct nose-tobrain transport. These systems enhance brain targeting while reducing systemic exposure and adverse effects. Various nanocarriers such as SLNs, NLCs, nanoemulsions, and liposomes have demonstrated improved permeability, sustained release, and therapeutic efficacy.
Voltage-gated sodium channels (VGSCs; Nav1.1-Nav1.9) are necessary for the initiation and propagation of action potentials in neurons, cardiac muscle and skeletal muscle. Because of their functional importance, VGSCs have become promising candidates for drug development in the brain, heart, and pain. The aim of this review is to highlight the structure, physiological role and pathological involvement of VGSCs in several different diseases, such as epilepsy, arrhythmias, chronic pain and cancer. Clinically established VGSC-targeting drugs are discussed, as well as recent evidence that shows an involvement of VGSCs in tumor progression and metastasis. Lack of selectivity, blood-brain barrier penetration, and regulatory complexities are among the challenges faced by VGSC-targeted therapy, as discussed in the review. Other challenges with VGSC-targeted therapy, such as high isoform homology, limited selectivity, blood-brain barrier penetration, and regulatory complexities, are also discussed in the review. In addition, new isoform-specific modulation strategies, innovative drug delivery devices, and new therapeutic approaches are highlighted. In summary, VGSCs are interesting but complex therapeutic targets, and future progress in selective targeting and drug delivery will likely increase their potential use across a variety of neurological, cardiovascular, and oncological disorders.
Neuroinflammation is a physiological response triggered by alterations in tissue homeostasis within the Central Nervous System (CNS); depending on the magnitude and chronicity of inflammation, it is considered a common state in the pathophysiology of several neurodegenerative and psychiatric diseases. Neuroinflammation is a very complex and context-dependent condition, mediated by the activity of several pathways and molecules, thus the search of valuable targets and therapeutic strategies is a priority. This study proposes a systems biology approach to create a data network about genes, drugs, and related targets in the context of human neuroinflammation to identify new potential repurposed drug candidates. Each candidate drug was associated with a score that considered both the topological properties of the network and the biological functions of the proteins. The computational pipeline identified Fostamatinib as a potential repurposed candidate in neuroinflammation. To confirm the computational results, R406, the active metabolite of Fostamatinib inhibiting the Syk pathway, was assessed in two different human microglial in vitro models to verify its potential beneficial effects. Results evidenced the efficacy of R406 in counteracting the pro-inflammatory response in both models.
The Blood-Brain Barrier (BBB) poses a formidable challenge for drug delivery to the Central Nervous System (CNS) due to its selective permeability and robust defense mechanisms. This review provides a comprehensive examination of the anatomical structure, physiology, and physiological challenges of the BBB, along with innovative approaches for overcoming these barriers to enhance CNS drug delivery. The BBB is primarily composed of endothelial cells, pericytes, and astrocytic end-feet, reinforced by tight junctions that tightly regulate the passage of substances into the brain parenchyma. Various transport mechanisms, including carrier-mediated transport, receptor-mediated transport (e.g., via LDL and transferrin receptors), absorptive-mediated transport, and active efflux transport, govern the selective influx and efflux of molecules across the BBB to maintain CNS homeostasis. Biological approaches harness endogenous transport mechanisms to facilitate drug delivery across the BBB, while chemical approaches leverage nanotechnology to engineer nanoparticles capable of traversing the barrier. These include liposomes, solid-lipid nanoparticles, polymeric nanoparticles, and inorganic nanoparticles, each designed with specific parameters such as particle size, shape, and surface charge to optimize drug delivery. Drug loading strategies, such as covalent bonding and non-covalent adsorption, enhance the encapsulation and release of therapeutic agents from nanoparticles. Furthermore, the incorporation of ligands facilitates receptor targeting and protein corona formation, enhancing nanoparticle properties and improving BBB penetration. By synthesizing recent advancements in BBB permeation strategies, this review aims to provide insights into the development of effective therapies for neurological disorders, ultimately advancing the field of CNS drug delivery.
Circadian rhythms are intrinsic time-keeping mechanisms that play a critical role in tuning immunity. Here, we investigated the impact of circadian rhythms on the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis (MS). We demonstrate that circulating neutrophils in blood significantly increase early in EAE, prior to symptoms onset. Importantly, we found that these cells infiltrate the central nervous system (CNS) in a time-of-day (ToD)-dependent manner, with increased infiltration at the onset of the behavioral active phase of the mice (evening). Transcriptomic analysis of CNS-infiltrating neutrophils revealed distinct ToD-dependent gene expression profiles, which identified Formyl peptide receptor 2 (FPR2) as a potential therapeutic candidate, since pharmacological inhibition of FPR2 led to reduced EAE disease severity. Furthermore, combinatorial treatment with a drug that targets VLA-4 (used in clinical practice under the trade name Natalizumab to treat MS) led to additive effects, substantially reducing EAE symptoms. Together, these findings highlight the importance of circadian immune cell dynamics during EAE development and provide a characterization of the circadian immune landscape in an animal model of MS, identifying potential targets for MS therapies.
To identify and verify new drug targets for focal epilepsy. We combined single-cell expression data from GSE190452, with genetic data from the eQTLGen alliance and utilized expression-associated single nucleotide polymorphism as an instrumental variable in Mendelian randomization analysis to investigate the causal link between gene expression and focal epilepsy risk. Moreover, co-localization analysis was used to evaluate the genetic mediating effect of gene expression. Potential drug interaction mechanisms involving the protein products of key genes were explored using molecular docking technology. The results were verified using an animal model of temporal lobe epilepsy. The results of Mendelian randomization analysis found that four genes (CASP1, FST, IL10RA, and SUCNR1) were significantly associated with focal epilepsy risk in the FinnGen and UK Biobank cohorts. However, only SUCNR1 (odds ratio [OR] = 0.462; 95% confidence interval [95% CI]: 0.240-0.890; p = 0.021) and IL10RA (OR = 0.719; 95% CI: 0.547-0.945; p = 0.018) showed consistent negative correlation, indicating that they may have a protective effect (OR < 1). Meanwhile, CASP1 (OR = 1.260; 95% CI: 1.023-1.553; p = 0.030) and FST (OR = 1.377; 95% CI: 1.044-1.816; p = 0.024) were associated with increased risk (OR > 1). CASP1, FST, IL10RA, and SUCNR1 are potential druggable genes and promising therapeutic targets for focal epilepsy treatment.
Neuroinflammation has emerged as an important pathogenic factor in central nervous system (CNS) disease, including various neurodegenerative diseases, brain injuries, and autoimmune conditions, affecting approximately 3 billion people worldwide. Mitochondrial dysfunction within neurovascular unit (NVU) cells not only initiates neuronal damage and blood-brain barrier (BBB) disruption but also critically reprograms immunometabolism, shifting microglia and infiltrating immune cells toward a pro-inflammatory, glycolysis-dominant state while impairing anti-inflammatory, oxidative phosphorylation-dependent functions. This metabolic rewiring fuels a vicious, self-amplifying cycle between mitochondrial impairment and sustained neuroinflammation. Consequently, targeting mitochondrial dysfunction has therefore emerged as a promising therapeutic strategy for controlling neuroinflammation. However, the double-membrane structure of mitochondria, coupled with the restrictive BBB, imposes formidable barriers to therapeutic delivery. Nanomedicine offers unprecedented opportunities. Advanced nanodrugs, engineered with mitochondrial-targeting ligands, stimuli-responsive materials, or biomimetic coatings, enable precise delivery of therapeutics directly to impaired mitochondria within the CNS. This review summarizes recent advances in mitochondrial dysfunction-induced neuroinflammation, highlights emerging nanotechnology-based mitochondrial targeting strategies in various CNS diseases, and discusses the existing challenges and future perspectives for translating these approaches into effective CNS therapies.
Neurodegenerative diseases frequently co-occur with skeletal muscle atrophy, creating a complex comorbid condition that significantly accelerates functional decline and increases mortality. This dual pathology is driven by interconnected mechanisms such as protein aggregation, neuroinflammation, and impaired axonal transport, disrupting critical neuromuscular junctions (NMJs). However, a significant research gap exists in the development of therapeutic strategies that can effectively and simultaneously target both the central nervous system (CNS) and peripheral muscle tissues. We systematically summarizes the core pathological targets and critically evaluates recent advances in precision drug delivery systems designed to overcome these challenges. We explore innovative strategies, including engineered viral vectors and receptor-targeted nanoparticles for CNS delivery, as well as smart biomaterials and extracellular vesicles (EVs) for muscle-specific and dual-organ intervention, highlighting the growing role of artificial intelligence (AI) in optimizing their design. Furthermore, this review discusses the construction of multidimensional efficacy evaluation systems that integrate behavioral, molecular, and imaging biomarkers and addresses pivotal clinical translation challenges, from scalable production to species-specific differences. By examining the pathological landscape across the central nervous system and skeletal muscle together, this review connects mechanisms that have more often been considered in isolation and evaluates how their convergence may inform the design of delivery strategies targeting both tissue compartments.