Search Results (1,134)

Demyelinating diseases comprise a group of chronic and debilitating neurological disorders, with the destruction of the myelin sheath serving as the core pathological hallmark. The central pathogenesis involves immune-mediated damage to oligodendrocytes (Ols) and myelin breakdown, accompanied by a vicious cycle of neuroinflammation and impaired epigenetic repair. Current therapeutic strategies, including conventional immunomodulatory agents to targeted monoclonal antibodies, effectively control disease relapses but exhibit limited efficacy in promoting neural repair. Consequently, research focus is increasingly shifting towards neuroprotective and remyelination strategies. In this context, Emerging therapeutic promise stems primarily from two fronts: the advent of novel pharmaceuticals, such as remyelination-promoting drugs targeting oligodendrocyte maturation, interventions inhibiting epigenetic silencing, signal pathway inhibitors, and natural products derived from traditional Chinese medicine; the development of innovative technologies, including cell therapies, gene therapy, exosome and nanoparticle-based drug delivery systems, as well as extracellular protein degradation platforms. Nevertheless, drug development still faces challenges such as disease heterogeneity, limited blood–brain barrier penetration, long-term safety, and difficulties in translating findings from preclinical models. Future efforts should emphasize precision medicine, multi-target synergistic therapies, and the development of intelligent delivery systems, with the ultimate goal of achieving a paradigm shift from delaying disability progression to functional neural reconstruction. Full article

Pediatric drug delivery presents unique challenges due to physiological and pharmacological differences across age groups, requiring specialized formulation approaches beyond simple dose adjustments of adult medications. This review synthesizes recent advances in polysaccharide-based pediatric drug delivery and highlights novel findings that may accelerate clinical translation. It summarizes how chitosan, alginate, hyaluronic acid, dextran, modified starches, and other polysaccharides are engineered into nanoparticles, hydrogels, films, and orodispersible/mini-tablet formulations to improve stability, bioavailability, taste masking, and controlled release across neonates to adolescents. These systems can accommodate developmental variations in absorption, distribution, metabolism, and excretion processes across pediatric subpopulations, with particular emphasis on oral and alternative administration routes. Evidence supporting unexpectedly high acceptability of mini-tablets, successful integration of modified polysaccharides in 3D-printed personalized low-dose therapies, and the emergence of blood–brain barrier-penetrating and RGD-functionalized polysaccharide nanocarriers for pediatric oncology are emphasized as novel, clinically relevant trends. This review also addresses regulatory considerations, safety profiles, and future perspectives. By integrating developmental insights with innovative formulation strategies, polysaccharide polymers offer promising solutions to improve medication adherence, safety, and efficacy across the pediatric age spectrum. Full article

Background/Objectives: Oral administration remains the most widely used route for drug delivery but is unsuitable for many central nervous system (CNS) therapeutics due to extensive hepatic first-pass metabolism and the restrictive blood–brain barrier (BBB). Acetyl salicylic acid (ASA), despite its neuroprotective and anti-inflammatory potential, exhibits poor brain bioavailability when delivered orally, limiting its therapeutic utility in ischemic stroke and chronic neurodegenerative conditions. Methods: This study reports the first use of three-dimensional (3D) bioprinting to develop brain-targeting ASA nanoparticle (NP)-loaded orally disintegrating films (ODFs) for direct systemic uptake and enhanced CNS delivery. The ODFs were fabricated using a CELLINK INKREDIBLE plus^® bioprinter and optimized for uniformity, rapid dissolution, and nanoparticle stability. Results: The films displayed consistent physicochemical properties (weight 10.86 ± 0.28 mg; thickness 0.47 ± 0.26 mm; pH 7.5–7.7) and disintegrated within 2.38 ± 0.28 min. In vitro testing on BEND3 brain endothelial cells confirmed biocompatibility, with no inflammatory response or cytotoxicity up to 62 µg/mL. In vivo biodistribution in murine models demonstrated substantial brain accumulation, achieving 14.15 ng/mg tissue following buccal administration. Conclusions: This work establishes a novel, non-invasive CNS drug delivery platform combining 3D bioprinting with ligand-functionalized ASA NPs to bypass hepatic metabolism and improve brain targeting. The rapid-dissolving ODFs demonstrated high reproducibility, safety, and effective brain deposition, highlighting their translational potential for neurological therapeutics. This approach may be extended to other small molecules with limited CNS penetration, offering a versatile pathway toward precision neuropharmacology. Full article

Objective: To develop a stable nanoemulsion loaded with Magnoliae Flos essential oil (MEO-NE) and evaluated its potential as an enhancer for nose-to-brain delivery in both solution and gel formulations. Methods: The MEO-NE was prepared using a low-energy emulsification method, with the formulation optimized via single-factor experiments and Box–Behnken design-response surface methodology. The optimized MEO-NE was characterized for particle size, PDI, morphology, and nasal mucosal irritation. Ex vivo histological imaging in rats was performed using hydrophilic sulfo-cyanine7 carboxylic acid and lipophilic coumarin 6 as fluorescent probes to assess distribution and retention in the trigeminal nerve and brain tissues. Results: The optimized MEO-NE exhibited a small particle size (27.96 ± 0.94 nm), low PDI (0.089 ± 0.013), spherical morphology, a stable O/W structure, and no irritation to the nasal mucosa. Ex vivo imaging revealed that MEO-NE significantly enhanced the distribution and retention of both hydrophilic and lipophilic probes in the trigeminal nerve and brain tissues. Moreover, the gel formulation of MEO-NE demonstrated superior brain-targeting efficiency over the solution within 6 h. Conclusions: MEO-NE served as an effective enhancer for nose-to-brain delivery, improving brain uptake of both hydrophilic and lipophilic drugs, and provided an experimental basis for utilizing herbal essential oils in CNS-targeted delivery systems. Full article

Neurodegenerative diseases, traumatic brain injuries, and strokes are accompanied by the development of secondary damage—a long-term pathological cascade in which cerebrospinal fluid (CSF) plays a key role. Unlike primary damage, which is acute, secondary processes can progress over months and even years, creating a therapeutic window for neuroprotection. CSF acts not simply as a passive medium but as an active mediator of the spread of cytotoxic factors—reactive oxygen species, glutamate, proinflammatory cytokines, pathological protein aggregates (Aβ, α-synuclein, tau, etc.), and exosomes—which transport toxic molecules between brain regions. These processes are exacerbated by dysfunction of the blood-brain and blood–cerebrospinal fluid barriers, leading to the accumulation of damaging agents in the CSF and accelerated neurodegeneration. This review examines the molecular mechanisms of secondary injury, the role of barrier systems in maintaining CSF homeostasis, and current therapeutic strategies aimed at modulating CSF composition. Particular attention is paid to innovative approaches to drug delivery to the central nervous system—from bispecific antibodies and nanoparticles to invasive techniques such as immunoselective CSF aspiration and nanoporous implants. The potential of CSF as a source of diagnostic biomarkers and as a therapeutic target for personalized treatment of neurodegenerative conditions is highlighted. Full article

The way in which Aquaporin-4 (AQP4) is localized on the astrocytes’ surface—i.e., with AQP4 channels predominantly located on the endfeet of astrocytes near the blood vessels—represents an important structural element for maintaining brain fluid homeostasis. In addition to this structural function, AQP4 polarity also facilitates glymphatic transport, the maintenance of the blood–brain barrier (BBB) functions, ion buffering, and neurotransmitter removal, and helps regulate neurovascular communications. The growing body of literature suggests that the loss of AQP4 polarity—a loss in the organization of AQP4 channels to the perivascular membrane—is associated with increased vascular, inflammatory, and metabolic disturbances in the context of many neurological diseases. As a result, this review attempts to synthesize both experimental and clinical studies to highlight that AQP4 depolarization often occurs in conjunction with early signs of neurodegeneration and neuroinflammation; however, we are aware that the loss of AQP4 polarity is only one factor in a complex pathophysiological environment. This review examines the molecular structure responsible for maintaining the polarity of AQP4—such as dystrophin–syntrophin complexes, orthogonal particle arrays, lipid microdomains, trafficking pathways, and transcriptional regulators—and describes how the vulnerability of these systems to various types of vascular stress, inflammatory signals, energy deficits, and mechanical injury can lead to a loss of AQP4 polarity. Furthermore, we will explore how a loss of AQP4 polarity can lead to the disruption of perivascular fluid movement, changes in blood–brain barrier morphology, enhanced neuroimmune activity, changes in ionic and metabolic balance, and disruptions in the global neural network synchronization. Importantly, we recognize that each of these disruptions will likely occur in concert with other disease-specific mechanisms. Alterations in AQP4 polarity have been observed in a variety of neurological disorders including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, traumatic brain injury, and glioma; however, we also observe that the same alterations in fluid regulation occur across all of these different diseases, but that no single upstream event accounts for the alteration in polarity. Ultimately, we will outline emerging therapeutic avenues to restore perivascular fluid transport, and will include molecular-based therapeutic agents designed to modify the anchoring of AQP4, methods designed to modulate the state of astrocytes, biomaterials-based drug delivery systems, and therapeutic methods that leverage dynamic modulation of the neurovascular interface. Future advances in multi-omic profiling, spatial proteomics, glymphatic imaging, and artificial intelligence will allow for earlier identification of AQP4 polarity disturbances and potentially allow for the development of more personalized treatment plans. Ultimately, by linking these concepts together, this review aims to frame AQP4 polarity as a modifiable aspect of the “fluidic connectome”, and highlight its importance in maintaining overall brain health across disease states. Full article

Background: Antibodies that cross the blood–brain barrier (BBB) by targeting receptor-mediated transport (RMT) systems can allow efficient drug delivery to the central nervous system (CNS). In order to improve brain uptake of antibodies, their binding properties have been engineered, but it is not always clear what antibody properties dictate BBB transport efficiency. In this study, we therefore developed and employed an in vitro phenotypic screen and a quantitative transcytosis assay in an attempt to identify improved variants of a previously identified BBB transcytosing antibody known as 46.1. Methods: First, a random mutagenic 46.1 antibody phage display library was screened for improved transcytosis through a human induced pluripotent stem cell (iPSC)-derived BBB model. These screens yielded antibody variants that enriched over multiple screening rounds; however, when produced as soluble antibodies, the variants did not display improved in vitro transcytosis over the wild-type (WT) 46.1 antibody. As a second strategy, we performed a targeted histidine point mutation of a solvent-exposed residue in each complementarity-determining region (CDR) and evaluated the in vitro transcytosis capacity of the variants. Results and Conclusions: In this way, we identified a 46.1 variant, R162H, with modestly improved in vitro transcytosis properties. These results show that the iPSC-derived BBB screening insights and evaluation strategies presented here could facilitate the engineering and optimization of lead antibodies for CNS delivery. Full article

Biomimetic cell membrane-coated nanoparticles (BMCNPs) are an attractive drug delivery platform that combines the advantages of an inorganic core with the biological functionality of a natural cell membrane. This hybrid design merges the versatility of engineered nanomaterials with the complexity and specificity of biological systems, enabling prolonged circulation, immune evasion, enhanced tissue targeting, and improved therapeutic efficacy. In this review, we explore the in vivo behavior of BMCNPs, focusing on their interactions with biological barriers, including evasion of mononuclear phagocyte system clearance, biodistribution patterns, and circulation kinetics. We also examine how membrane source and surface properties influence targeting efficiency and delivery outcomes, while highlighting key considerations and emerging strategies to optimize therapeutic performance and translational potential. Full article

RNA interference (RNAi) offers programmable, sequence-specific silencing via small interfering RNA (siRNA) and microRNA (miRNA), but clinical translation hinges on overcoming instability, immunogenicity, and inefficient endosomal escape. This review synthesizes advances in non-viral nanocarriers—liposomes, polymeric nanoparticles, and extracellular vesicles (EVs)—that stabilize nucleic acids, tune biodistribution, and enable organ- and cell-selective delivery. We highlight design levers that now define the field: ligand-guided targeting, stimuli-responsive release, biomimicry and endogenous carriers, and rational co-delivery with small molecules. Across major disease areas—cancer and cardiovascular, respiratory, and urological disorders—these platforms achieve tissue-selective uptake (e.g., macrophages, endothelium, and myocardium), traverse physiological barriers (including the blood–brain barrier and fibrotic stroma), and remodel hostile microenvironments or immune programs to enhance efficacy while maintaining favorable safety profiles. Early clinical studies reflect this diversity, spanning targeted nanoparticles, local drug depots, exosome and cellular carriers, and inhaled formulations, e.g., and converge on core phase-I endpoints (safety, maximum tolerated dose, pharmacokinetics/pharmacodynamics, and early activity). Looking ahead, priorities include good manufacturing practice scale, consistent manufacture—especially for EVs; more efficient loading and cargo control; improved endosomal escape and biodistribution; and rigorous, long-term safety evaluation with standardized, head-to-head benchmarking. Emerging directions such as in vivo EVs biogenesis, theragnostic integration, and data-driven formulation discovery are poised to accelerate translation. Collectively, nanoparticle-enabled RNAi has matured into a versatile, clinically relevant toolkit for precise gene silencing, positioning the field to deliver next-generation therapies across diverse indications. Full article

(1) Background: Glioblastoma is the most common and aggressive primary brain tumor in adults, with a median survival time for patients treated with standard chemotherapy often of less than 1 year. Potential anticancer activity against glioblastoma is demonstrated by flavonoids, including fisetin (FIS). Although, its clinical application is limited by poor solubility and chemical instability. This study aimed to conduct a preliminary evaluation of fisetin’s suitability for intravenous delivery by developing and characterizing FIS-loaded poly(lactic-co-glycolic acid) nanoparticles (FIS-PLGA-NPs) and assessing their in vitro cytotoxic potential against glioblastoma. (2) Methods: Six FIS-PLGA nanoparticle formulations were prepared via the emulsification–solvent evaporation method and evaluated for key physicochemical properties. The biological activity of fisetin was examined through cell cycle analysis and apoptosis assays, and the most promising formulation was further assessed using an MTT assay in U-138 MG glioblastoma cells. In parallel, pure fisetin was exposed to ionizing radiation, including the standard sterilization dose of 25 kGy, to evaluate its structural stability and suitability for terminal sterilization approaches. (3) Results: The selected formulation (NP4) exhibited a mean particle size of approximately 330 nm, a zeta potential of −7.2 mV, a polydispersity index of 0.25, and high encapsulation efficiency and drug loading of 83.58% and 13.93%, respectively. Despite its preliminary nature, this formulation retained cytotoxic activity in vitro. Moreover, pure fisetin maintained its structural and chemical integrity following radiation exposure, supporting the feasibility of radiation sterilization prior to nanoparticle incorporation. (4) Conclusions: These findings confirm the feasibility of combining radiosterilizable fisetin with PLGA-based nanoencapsulation and provide an initial foundation for the development of an injectable fisetin delivery system for glioblastoma treatment. Further optimization, particularly surface modification, will be required to enhance colloidal stability and systemic performance. Full article

The blood–brain barrier (BBB) represents a major challenge in effective drug delivery systems intended for treating neurological disorders. It restricts the transport of therapeutic agents to the brain. Chitosan-based nanoparticles (CNPs) can be used for brain drug delivery because of their biocompatibility, biodegradability, and ability to enhance drug permeability across the BBB. This review article discusses the design and application of CNPs for brain-targeted drug delivery, exploring their mechanisms of action, including adsorptive-mediated and receptor-mediated endocytosis. Surface modifications with ligands such as chlorotoxin are discussed for improving specificity and therapeutic results. Findings show that CNPs allow controlled drug release, enhance stability, and reduce side effects, which make them effective for treating multiple neurological conditions, including Alzheimer’s disease, Parkinson’s disease, brain tumors, and ischemic stroke. CNPs can encapsulate multiple therapeutic agents, such as anti-inflammatory drugs, cytotoxic agents, and genetic materials, and maintain stability under different physiological conditions. Intranasal delivery routes are mainly discussed in this paper for their ability to bypass systemic circulation and achieve direct brain targeting. This review also addresses challenges such as cytotoxicity and the need for optimizing nanoparticle size, charge, and surface properties to improve the therapy results. While CNPs are suitable for brain drug delivery, there is a research gap, which is the lack of systematic studies evaluating their long-term effects on brain tissue and health. Most studies focus on acute therapeutic outcomes and in vitro or short-term in vivo analysis, which do not address some questions about the chronic exposure risks, biodistribution, and clearance pathways of CNPs. This review also explores the use of chitosan-based nanoparticles to deliver drugs to the brain for the treatment of multiple neurological disorders. Full article

Alzheimer’s disease (AD), the leading cause of dementia, is defined by two pathological hallmarks, amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles—both now structurally resolved at near-atomic precision thanks to cryo-EM. Despite decades of research, effective disease-modifying therapies remain elusive, underscoring the need for innovative interdisciplinary approaches. This review synthesizes recent advances in structural biology and nanotechnology, highlighting their synergistic potential in revolutionizing AD diagnosis and treatment. Cryo-EM and NMR have revolutionized our understanding of Aβ/tau polymorphs, revealing structural vulnerabilities ripe for therapeutic targeting—yet clinical translation remains bottlenecked by the blood–brain barrier (BBB). Concurrently, nanotechnology offers groundbreaking tools, including nanoparticle-based drug delivery systems for blood–brain barrier (BBB) penetration, quantum dot biosensors for early Aβ detection, and CRISPR-nano platforms for APOE4 gene editing. We discuss how integrating these disciplines addresses critical challenges in AD management—from early biomarker detection to precision therapeutics—and outline future directions for translating these innovations into clinical practice. Full article

Background/Objectives: Glioblastoma, the most common primary tumor of the central nervous system, is characterized by high malignancy and poor prognosis. One of the main challenges in neurological disorders is to develop an effective treatment modality that can cross the blood–brain barrier. Nanoparticles are revolutionary for neurodegenerative diseases due to their targeted delivery and ability to overcome biological barriers. Cerium oxide (Ce₂O₃) nanoparticles are suitable for use as drug delivery systems. Methods: In our study, we investigated the anticancer mechanism using SN-38, lithium, and Ce₂O₃, a powerful agent used in GBM treatment. We evaluated their anticancer activities separately and in combination with U373 cell lines. GBM cell line U373 cells were cultured. Then, all groups except the control group were treated with different doses of SN-38 and lithium combination therapy with SN-38, lithium, and Ce₂O₃ combination therapy. The results were evaluated using MTT and ELISA tests. Results: When the results were examined, anticancer activity was detected at PTEN, AKT, mTOR, and BAX/Bcl-2 levels in the SN-38 + NPs 25 µg/mL + Lithium 50 µg/mL and SN-38 + NPs 50 µg/mL + Lithium 50 µg/mL dose groups. In addition, findings that inflammation markers were correlated with the apoptosis mechanism were obtained. Conclusion: This study is the first to report that combining lithium with SN-38 and NPs increased oxidative stress more than lithium with SN-38, leading glioblastoma cells to apoptosis and its potential anticancer activity. These results provide a basis for further investigation of its clinical application in cancer treatment. Full article

In this study, we review the use of cyclodextrin-based formulations to develop oral tablets of cladribine by enhancing its bioavailability and to improve the solubility and stability of retrometabolic chemical delivery systems (CDSs) in general and estredox, a brain-targeting estradiol-CDS, in particular. Cyclodextrins (CDs), cyclic oligosaccharides that can form host–guest inclusion complexes with a variety of molecules, are widely utilized in pharmaceuticals to increase drug solubility, stability, bioavailability, etc. The stability of the complex depends on how well the guest fits within the cavity of the CD host; a model connecting this to the size of the guest molecules is briefly discussed. Modified CDs, and particularly 2-hydroxypropyl-β-cyclodextrin (HPβCD), provided dramatically increased water solubility and oxidative stability for estredox (estradiol-CDS, E₂-CDS), making its clinical development possible and highlighting the potential of our brain-targeted CDS approach for CNS-targeted delivery with minimal peripheral exposure. A unique HPβCD-based formulation also provided an innovative solution for the development of orally administrable cladribine. The corresponding complex dual CD-complex formed by an amorphous admixture of inclusion- and non-inclusion cladribine–HPβCD complexes led to the development of tablets that provide adequate oral bioavailability for cladribine, as demonstrated in both preclinical and clinical studies. Cladribine–HPβCD tablets (Mavenclad) offer a convenient, effective, and well-tolerated oral therapy for multiple sclerosis, achieving worldwide approval and significant clinical success. Overall, the developments summarized here underscore the importance of tailored cyclodextrin-based approaches for overcoming barriers in drug formulation for compounds with challenging physicochemical properties, and demonstrate the versatility and clinical impact of CD inclusion complexes in modern pharmaceutical development. Full article

Neurological damage, a debilitating condition closely associated with chronic neuroinflammation, currently lacks disease-modifying treatments, with management limited to symptomatic relief. Vitamins B6 (VB6), B12 (VB12), and proteolipid protein 1 (PLP-1) exhibit multimodal neuroprotective and anti-inflammatory effects; however, their therapeutic potential is limited by low bioavailability and inadequate ability to cross the blood–brain barrier (BBB). To address these limitations, we developed an ursolic acid-based nanoparticle system for the intranasal co-delivery of VB6, VB12, and recombinant PLP-1. The PLP-1 model predicted by AlphaFold3 was used for molecular docking. The docking results confirmed high-affinity binding interactions with VB6 and VB12, elucidating the mechanistic basis of their synergy. In vitro studies using a glucose-deprived PC12 cell injury model identified an optimal synergistic molar ratio of 10:1:2 (VB6: VB12: PLP-1). This combination significantly upregulated neuroprotective markers (PLP-1 and PGC-1α) and downregulated the pro-inflammatory cytokine TNF-α. In a mouse model of neural damage, the nano-encapsulated combination therapy demonstrated improved pharmacokinetics and significantly attenuated neuroinflammation and oxidative stress in brain tissue. This was evidenced by lower TNF-α and IL-1β levels and elevated GSH and SOD concentrations compared to free drug controls. The treatment regimen showed no detectable hepatorenal toxicity. Our findings demonstrate that this nanoformulation represents a safe, effective, and promising disease-modifying strategy to treat vestibular dysfunction by synergistically targeting its underlying neuroimmunological mechanisms. Full article