Search Results (147)

Central nervous system (CNS) disorders present significant therapeutic challenges due to the limited regenerative capacity of neural tissues, resulting in long-term disability for many patients. Consequently, the development of novel therapeutic strategies is urgently warranted. Stem cell therapies show considerable potential for mitigating brain damage and restoring neural connectivity, owing to their multifaceted properties, including anti-apoptotic, anti-inflammatory, neurogenic, and vasculogenic effects. Recent research has also identified exosomes—small vesicles enclosed by a lipid bilayer, secreted by stem cells—as a key mechanism underlying the therapeutic effects of stem cell therapies, and given their enhanced stability and superior blood–brain barrier permeability compared to the stem cells themselves, exosomes have emerged as a promising alternative treatment for CNS disorders. A key challenge in the application of both stem cell and exosome-based therapies for CNS diseases is the method of delivery. Currently, several routes are being investigated, including intracerebral, intrathecal, intravenous, intranasal, and intra-arterial administration. Intracerebral injection can deliver a substantial quantity of stem cells directly to the brain, but it carries the potential risk of inducing additional brain injury. Conversely, intravenous transplantation is minimally invasive but results in limited delivery of cells and exosomes to the brain, which may compromise the therapeutic efficacy. With advancements in catheter technology, intra-arterial administration of stem cells and exosomes has garnered increasing attention as a promising delivery strategy. This approach offers the advantage of delivering a significant number of stem cells and exosomes to the brain while minimizing the risk of additional brain damage. However, the investigation into the therapeutic potential of intra-arterial transplantation for CNS injury is still in its early stages. In this comprehensive review, we aim to summarize both basic and clinical research exploring the intra-arterial administration of stem cells and exosomes for the treatment of CNS diseases. Additionally, we will elucidate the underlying therapeutic mechanisms and provide insights into the future potential of this approach. Full article

The intranasal delivery of exogenous mitochondria is a potential therapy for Parkinson’s disease (PD). The regulatory mechanisms and effectiveness in genetic models remains uncertain, as well as the impact of modulating the mitochondrial permeability transition pore (mPTP) in grafts. Utilizing UQCRC1 (p.Tyr314Ser) knock-in mice, and a cellular model, this study validated the transplantation of mitochondria with or without cyclosporin A (CsA) preloading as a method to treat mitochondrial dysfunction and improve disease progression through intranasal delivery. Liver-derived mitochondria were labeled with bromodeoxyuridine (BrdU), incubated with CsA to inhibit mPTP opening, and were administered weekly via the nasal route to 6-month-old mice for six months. Both treatment groups showed significant locomotor improvements in open-field tests. PET imaging showed increased striatal tracer uptake, indicating enhanced dopamine synthesis capacity. The immunohistochemical analysis revealed increased neuron survival in the dentate gyrus, a higher number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN) and striatum (ST), and a thicker granule cell layer. In SN neurons, the function of mitochondrial complex III was reinstated. Additionally, the CsA-accumulated mitochondria reduced more proinflammatory cytokine levels, yet their therapeutic effectiveness was similar to that of unmodified mitochondria. External mitochondria were detected in multiple brain areas through BrdU tracking, showing a 3.6-fold increase in the ST compared to the SN. In the ST, about 47% of TH-positive neurons incorporated exogenous mitochondria compared to 8% in the SN. Notably, GFAP-labeled striatal astrocytes (ASTs) also displayed external mitochondria, while MBP-labeled striatal oligodendrocytes (OLs) did not. On the other hand, fewer ASTs and increased OLs were noted, along with lower S100β levels, indicating reduced reactive gliosis and a more supportive environment for OLs. Intranasally, mitochondrial transplantation showed neuroprotective effects in genetic PD, validating a noninvasive therapeutic approach. This supports mitochondrial recovery and is linked to anti-inflammatory responses and glial modulation. Full article

Donepezil (DPZ) is an Alzheimer’s disease (AD) drug that promotes cholinergic neurotransmission and exhibits excellent acetylcholinesterase (AChE) selectivity. The current oral formulations of DPZ demonstrate decreased bioavailability, attributed to limited drug permeability across the blood–brain barrier (BBB). In order to overcome these limitations, various dosage forms aimed at delivering DPZ have been explored. This discussion will focus on the nose-to-brain (N2B) delivery system, which represents the most promising approach for brain drug delivery. Intranasal (IN) drug delivery is a suitable system for directly delivering drugs to the brain, as it bypasses the BBB and avoids the first-pass effect, thereby targeting the central nervous system (CNS). Currently developed formulations include lipid-based, solid particle-based, solution-based, gel-based, and film-based types, and a systematic review of the N2B research related to these formulations has been conducted. According to the in vivo results, the brain drug concentration 15 min after IN administration was more than twice as high those from other routes of administration, and the direct delivery ratio of the N2B system improved to 80.32%. The research findings collectively suggest low toxicity and high therapeutic efficacy for AD. This review examines drug formulations and delivery methods optimized for the N2B delivery of DPZ, focusing on technologies that enhance mucosal residence time and bioavailability while discussing recent advancements in the field. Full article

Background/Objectives: In this study, we aimed to evaluate probiotics’ clinical efficacy and safety in adults with chronic rhinosinusitis (CRS), and summarize mechanistic evidence related to mucosal immunity and microbiota modulation. Methods: We performed a systematic review and random-effects meta-analysis. MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Library were searched until May 2025. Eligibility: Randomized controlled trials (RCTs) and mechanistic studies investigating probiotics (any strain, dose, or administration route) in adults with CRS were eligible. Primary outcomes included changes in Sino-Nasal Outcome Test (SNOT-20/22) scores and CRS relapse rates. Secondary outcomes were adverse events and mechanistic endpoints. Results: Six studies (four RCTs, n = 337; two mechanistic studies) met the inclusion criteria. Probiotics did not significantly improve SNOT scores compared with the placebo, but trended in that direction (pooled mean difference—2.70; 95% CI −7.12 to 1.72; I² = 0%). Furthermore, probiotic use was associated with a non-significant trend towards fewer CRS relapses (risk ratio 0.41; 95% CI 0.16–1.04; p = 0.06; I² = 48%). Adverse events were mild and comparable to the placebo (risk ratio 0.87; 95% CI 0.33–2.34). Mechanistic data indicated that intranasal Lactococcus lactis W136 might downregulate type 1 inflammatory pathways and modestly increase microbiome diversity. Subgroup analyses (by route, duration, and CRS subtype) revealed no statistically significant effect modifiers, though mechanistic insights suggest possible differences in efficacy based on the CRS endotype and delivery method. Conclusions: Probiotics appear safe and may provide a small, non-significant improvement in CRS symptoms; emerging evidence of reduced relapse rates warrants further investigation through larger, endotype-stratified trials utilizing targeted probiotic strains and optimized delivery methods. Full article

Nocardia, an easily missed but potentially fatal opportunistic pathogen, can lead to serious infections like lung and brain abscesses. Intranasal inoculation (IN) is the traditional approach for constructing a Nocardia-induced pneumonia mice model, while it usually only results in limited local bacterial infection in the lungs. To comprehensively assess infection dynamics across distinct pulmonary inoculation routes in mice models, this study compared the pathogenicity of three different Nocardia farcinica pneumonia models established via IN, intratracheal aerosolization (ITA), and intratracheal instillation (ITI). C57BL/6J mice were infected with N. farcinica through IN, ITA and ITI with comparative analyses of bacterial distribution in lungs, survival rate, weight, bacterial load, inflammatory cytokines, histopathological characteristics and transcriptome differences. The findings suggest that ITA N. farcinica infections caused severer clinical symptoms, higher mortality, pulmonary bacterial load, levels of inflammatory cytokines in bronchoalveolar lavage fluid, and more significant histopathological damage to lungs than IN and ITI. Furthermore, ITA resulted in better lung bacterial distribution and delivery efficiency than ITI and IN. Transcriptome analysis of lungs from N. farcinica infected mice via IN, ITA and ITI revealed significant differential gene expression, whereas ITA route resulted in a larger fold change. ITA provides a more consistent and severe model of N. farcinica pneumonia in mice than IN and ITI, which can make the bacteria more evenly distributed in the lungs, leading to more severe pathological damage and higher mortality rates. In conclusion, ITA is an optimal route for developing animal models of N. farcinica pneumonia infections. Full article

Background/Objectives: Non-invasive central nervous system (CNS) therapies are limited by complex mechanisms and the blood–brain barrier, but nasal delivery offers a promising alternative. The study planned to develop a non-invasive in situ intranasal mucoadhesive thermosensitive gel to deliver CNS-active risperidone via nose-to-brain targeting. Risperidone, a second-generation antipsychotic, has shown efficacy in managing both psychotic and mood-related symptoms. The mucoadhesive gel formulations help to prolong the residence time at the nasal absorption site, thereby facilitating the uptake of the drug. Methods: The poloxamer 407 (18.0% w/v), HPMC K100M and K15M (0.3–0.5% w/v), and benzalkonium chloride (0.1% v/v) were used as thermosensitive polymers, a mucoadhesive agent, and a preservative, respectively, for the development of in situ thermosensitive gel. The developed formulations were evaluated for various parameters. Results: The pH, gelation temperature, gelation time, and drug content were found to be 6.20 ± 0.026–6.37 ± 0.015, 34.25 ± 1.10–37.50 ± 1.05 °C, 1.65 ± 0.30–2.50 ± 0.55 min, and 95.58 ± 2.37–98.03 ± 1.68%, respectively. Furthermore, the optimized F3 formulation showed satisfactory gelling capacity (9.52 ± 0.513 h) and an acceptable mucoadhesive strength (1110.65 ± 6.87 dyne/cm²). Diffusion of the drug through the egg membrane depended on the formulation’s viscosity, and the F3 formulation explained the first-order release kinetics, indicating concentration-dependent drug diffusion with n < 0.45 (0.398) value, indicating the Fickian-diffusion (diffusional case I). The pharmacokinetic study was performed with male Wistar albino rats, and the F3 in situ thermosensitive risperidone gel confirmed significantly (p < 0.05) ~5.4 times higher brain AUC_0–∞ when administered intranasally compared to the oral solution. Conclusions: Based on physicochemical, in vitro, and in vivo parameters, it can be concluded that in situ thermosensitive gel is suitable for administration of risperidone through the nasal route and can enhance patient compliance through ease of application and with less repeated administration. Full article

Nasal nanodrug delivery has gained prominence as a non-invasive method for administering therapeutic agents to the brain. However, the limited nasal cavity volume and the low drug loading capacity of nanoparticles contribute to a reduced accumulation of the drug within the brain tissue. Therefore, the aim of the present study was to investigate the role of the drug delivery combination “transnasal route + nanoparticle drug delivery system + chemical osmosis technology” in promoting drug accumulation in the brain. We constructed an in vitro olfactory sheath cell model based on the direct nose–brain pathway and a vascular endothelial cell model based on the indirect pathway, and investigated the transport behaviors and mechanisms of Poly(lactic-co-glycolicacid)-Nanoparticles (PLGA-NPs) in combination with two terpene aroma constituents (menthol and curcumol). Menthol and curcumol significantly improved the intracellular accumulation of PLGA-NPs, which may be related to changes in the endocytosis pathway and intercellular tight junction proteins. Meanwhile, the results of laser scanning confocal microscopy and atomic force microscopy showed that menthol and curcumol disrupted different tight junction proteins of vascular endothelial cells, and the biomechanical properties (e.g., rigidity and roughness) of the olfactory sheath cells and vascular endothelial cell cytomembranes were also greatly changed. The delivery system of “transnasal route + nanoparticle drug delivery system + chemical osmosis technology” has great potential for intranasal delivery of drugs for the treatment of brain diseases. Full article

Background: Agitation is a frequent and challenging symptom in schizophrenia and bipolar disorder, characterized by heightened motor activity, emotional distress, and potential aggression. This symptom is most observed during acute episodes, representing a significant burden on patients, caregivers, and healthcare systems. Agitation is a leading cause of emergency department visits and psychiatric hospitalizations, necessitating prompt and effective interventions to ensure safety and mitigate its far-reaching impact. Traditional treatments, including high-potency antipsychotics and benzodiazepines, remain first-line options but are associated with significant drawbacks such as sedation, extrapyramidal symptoms, tolerance, and limited applicability in certain patient populations, especially those with respiratory or cardiac depression and the elderly. Non-pharmacologic strategies like de-escalation techniques and environmental modifications are invaluable but may be impractical in acute care settings, as speed and efficiency are critical in emergent settings. These limitations, including the onset of extrapyramidal symptoms with high-dose antipsychotics and the development of tolerance with benzodiazepines, highlight gaps in care, including the need for faster-acting, safer, and more patient-friendly alternatives that reduce reliance on physical restraints and invasive interventions. Methods: This review explores the evolution of treatments for agitation, focusing on alternative and innovative approaches. To highlight these treatments, an extensive review of the literature was conducted utilizing PubMed, Google Scholar, Embase.com, and other search engines. Results: Key developments include sublingual dexmedetomidine, recently FDA-approved, which offers sedation without respiratory depression and a non-invasive administration route. Similarly, subcutaneous olanzapine provides a more convenient alternative to intramuscular injections, reducing injection-related complications. Other emerging treatments such as gabapentin, pregabalin, and ketamine show promise in addressing agitation in specific contexts, including comorbid conditions and treatment-resistant cases. A comparative analysis of these therapies highlights their mechanisms of action, clinical evidence, and practical challenges. Conclusions: Future directions emphasize intranasal delivery systems, novel pharmacologic agents, and potential roles for cannabinoids in managing agitation. These innovations aim to balance rapid symptom control with improved patient safety and experience. The set back with these emerging techniques is a lack of standardized dosing and protocols. They also face ethical concerns, including the chance of misuse or abuse, as well as regulatory barriers, as they lack FDA approval and their legality changes between states. This review underscores the clinical, practical, and ethical considerations in advancing care for agitated patients, paving the way for more effective and compassionate management strategies in psychiatric settings. Full article

Nano-drug delivery systems provide targeted solutions for addressing various drug delivery challenges, leveraging nanotechnology to enhance drug solubility and permeability. Liposomes, explored for several decades, face hurdles, especially in oral delivery. Bile-acid stabilized vesicles (bilosomes) are flexible lipid vesicles, composed of phospholipids or other surfactants, along with amphiphilic bile salts, and they show superior stability and pharmacokinetic behavior in comparison to conventional vesicular systems (liposomes and niosomes). Bilosomes enhance skin penetration, fluidize the stratum corneum, and improve drug stability. In oral applications, bilosomes overcome drawbacks, offering improved bioavailability, controlled release, and reduced side effects. Vaccines using bilosomes demonstrate efficacy, and bilosomes for intranasal, inhalation, ocular, and buccal applications enhance drug delivery, offering targeted, efficient, and controlled activities. Formulations vary based on active substances and optimization techniques, showcasing the versatility and potential of bilosomes across diverse drug delivery routes. Therefore, the aim of this comprehensive review was to critically explore the state-of-the-art of bilosomes in drug delivery and potential therapeutic applications. Full article

Poly(D,L-lactide-co-glycolide) (PLGA) has emerged as a cornerstone in the development of advanced drug delivery systems, particularly for intranasal and pulmonary routes. Its biodegradability, biocompatibility, and adaptability make it an ideal platform for addressing challenges associated with conventional therapies. By enabling sustained and controlled drug release, PLGA formulations reduce dosing frequency, improve patient compliance, and enhance therapeutic efficacy. These systems demonstrate versatility, accommodating hydrophilic and hydrophobic drugs, biological molecules, and co-delivery of synergistic agents. Moreover, surface modifications and advanced preparation techniques enhance targeting, bioavailability, and stability, expanding PLGA’s applications to treat complex diseases such as tuberculosis, cancer, pulmonary fibrosis, and CNS disorders. This manuscript provides an in-depth review of PLGA’s materials, properties, preparation methods, and therapeutic applications, alongside a critical evaluation of challenges and future opportunities in this field. Full article

Background: The neuroprotective efficacy of glibenclamide (GLIB) has been demonstrated in multiple rodent models of ischemia, hemorrhagic stroke, traumatic brain damage, spinal cord injury, and metastatic brain tumors. Due to its poor solubility, GLIB has low oral bioavailability, limiting its transportation to the brain via the oral route. Objectives: Here, we attempted to develop and optimize an intranasal mucoadhesive in situ gel of GLIB-loaded bilosomes using a 3² Box–Behnken design for brain drug delivery. Methods: To facilitate a longer residence time of the administered dose within the nasal cavity, the prepared bilosomes were loaded into a mucoadhesive in situ gel providing resistance to rapid mucociliary clearance. The amounts of sodium deoxycholate, the cholesterol/Span 40 mixture, and the molar ratio between the mixture’s components were chosen as independent variables, while the entrapment efficiency and in vitro drug release were selected as dependent variables. Results and conclusions: The optimal formulation was analyzed for particle size and entrapment efficiency, which were found to be 270.6 nm and 68.39%, respectively. In vitro drug release from optimal formulation after 12 h was 87.29 ± 1.98% as compared to 52.01 ± 2.04% of plain in situ gel of drug. An in vivo brain drug delivery study performed on Swiss albino mice showed that the brain concentration of drug through intranasal administration from mucoadhesive in situ gel of GLIB-bilosomes after 12 h was 2.12 ± 0.16 µg/mL as compared to 0.68 ± 0.04 µg/mL from plain in situ gel of drug. Conclusively, the developed bilosomal formulation offers a favorable intranasal substitute with enhanced therapeutic drug delivery to the brain. Full article

Background/Objectives: We generated a novel recombinant Vibrio cholerae ghost (rVCG)-based subunit vaccine incorporating the A1 subunit of cholera toxin (CTA1) and a multiepitope Chlamydia trachomatis (CT) antigen (MECA) derived from five chlamydial outer membrane proteins (rVCG-MECA). The ability of this vaccine to protect against a CT transcervical challenge was evaluated. Methods: Female C57BL/6J mice were immunized thrice at two-week intervals with rVCG-MECA or rVCG-gD2 (antigen control) via the intramuscular (IM) or intranasal (IN) route. PBS-immunized mice or mice immunized with live CT served as negative and positive controls, respectively. Results: Vaccine delivery stimulated robust humoral and cell-mediated immune effectors, characterized by local mucosal and systemic CT-specific IgG, IgG2c, and IgA antibody and IFN-γ (Th1 cytokine) responses. The elicited mucosal and systemic IgG2c and IgA antibody responses persisted for 16 weeks post-immunization. Immunization with rVCG-MECA afforded protection comparable to that provided by IN immunization with live CT EBs without any side effects, irrespective of route of vaccine delivery. Conclusions: The results underline the potential of a multiepitope vaccine as a promising resource for protecting against CT genital infection and the potential of CTA1 on the VCG platform as a mucosal and systemic adjuvant for developing CT vaccines. Full article

A challenge to contemporary medicine is still the discovery of an effective and safe therapy for symptomatic control, if not cure, of Parkinson’s disease. While the potential century’s break-through is sought and foreseen by many scientists in gene therapy, immunotherapy, new drug combinations, and neurosurgical approaches, the not-yet-conventional intranasal administration of “classic” levodopa (L-DOPA) also stands out as a perspective from which Parkinson’s patients may benefit in the short term. With the main drawbacks of the standard oral L-DOPA treatment being the extremely low systemic and cerebral bioavailability, it is widely recognized that the nasal route may turn out to be the better administration site, for it offers the alternative of direct brain delivery via the olfactory bulb (the so-called nose-to-brain axis). However, such advancement would be unthinkable without the current progress in nano-scaled drug carriers which are needed to ensure drug stability, mucosal retention and permeation, olfactory uptake, and harmlessness to the sensory neurons and respiratory cilia. This study aims to review the most significant results and achievements in the field of nano-particulate nose-to-brain delivery of L-DOPA. Full article

Background: Ketamine HCl, an FDA-approved therapeutic, is administered through various routes, including intranasal delivery. Administering an adequate therapeutic dose of intranasal ketamine HCl is challenging due to the limited volume that can be delivered intranasally given the current commercially available concentrations. Objectives: This study investigates solubilizing strategies to enhance the aqueous solubility of ketamine HCl for intranasal administration. Methods: We assessed the solubility profile of ketamine HCl by evaluating factors such as pH, co-solvents, and surfactants. Additionally, we developed and validated a UV-Vis spectroscopy method for ketamine HCl analysis. Results: Our solubility screening in various organic co-solvents revealed the following order of effectiveness in enhancing solubility: methanol > water > propylene glycol > ethanol > dimethyl sulfoxide (DMSO) > N-methyl-2-pyrrolidone (NMP). Despite methanol’s superior solubility, its potential toxicity, coupled with the relatively lower effectiveness of other solvents compared to water, suggests that a co-solvency approach is not advantageous for ketamine HCl. We found that ketamine HCl solubility increased with medium acidity, with pH 3.5 being the optimal for further formulation studies. The impact of pharmaceutical surfactants on ketamine HCl solubility at an acidic pH was also evaluated. Surfactants tested included SDS, PEG 400, PVP, Tween 20, poloxamer 188, and lecithin. Notably, PEG 400 and PVP reduced solubility due to a salting-out effect, whereas Tween 80, lecithin, and poloxamer 188 slightly improved solubility through micelle formation. Among the surfactants tested, 1% SDS emerged as the most effective in enhancing ketamine HCl solubility. Conclusions: These outcomes highlight the potential of these solubilization strategies to address the solubility limitations of ketamine HCl, enabling the preparation of highly concentrated ketamine HCl formulations for intranasal delivery. Full article

Background/objectives: The blood–brain barrier (BBB) significantly limits the treatment of central nervous system disorders, such as schizophrenia, by restricting drug delivery to the brain. This study explores the potential of intranasal clozapine-loaded lipid nanocapsules (IN LNCs_Clo) as a targeted and effective delivery system to the brain. Methods: LNCs_Clo were prepared using the phase inversion technique and characterized in terms of size, zeta potential, entrapment efficiency (EE%), and in vitro drug release. The pharmacokinetic, safety, and pharmacodynamic effects of LNCs_Clo were then evaluated in a rat model through intranasal (IN) administration and compared with those of oral and intravenous (IV) Clo solutions. Results: LNCs_Clo were prepared using a phase inversion technique, resulting in a nanocarrier with a particle size of 28.6 ± 3.6 nm, homogenous dispersion, and high EE% (84.66 ± 5.66%). Pharmacokinetic analysis demonstrated that IN LNCs_Clo provided enhanced Clo brain bioavailability, rapid CNS targeting, and prolonged drug retention compared to oral and intravenous routes. Notably, the area under the curve (AUC) for brain concentration showed more than two-fold and eight-fold increases with LNCs_Clo, compared to IV and oral solutions, respectively, indicating improved brain-targeting efficiency. Safety assessments indicated that LNCs_Clo administration mitigated Clo-associated metabolic side effects, such as hyperglycemia, insulin imbalance, and liver enzyme alterations. Additionally, pharmacodynamic studies showed that LNCs_Clo significantly improved antipsychotic efficacy and reduced schizophrenia-induced hyperactivity, while preserving motor function. Conclusions: These results highlight the potential of IN LNCs_Clo as a novel drug delivery system, offering improved therapeutic efficacy, reduced systemic side effects, and better patient compliance in the treatment of schizophrenia and potentially other CNS disorders. Full article