Search Results (666)

Background: The COVID-19 pandemic exposed critical gaps in pandemic preparedness and highlighted the need for vaccine platforms capable of rapid adaptation. Outer membrane vesicle (OMV)-based platforms utilizing vesicles derived from genetically detoxified Neisseria meningitidis serogroup B (Nm-nOMV) represent a promising plug-and-play approach. Methods: This Phase I, first-in-human, randomized, double-blind, placebo- and OMV-controlled trial, evaluated safety, tolerability, and immunogenicity of intranasally administered OMVs combined with SARS-CoV-2 Spike protein in healthy SARS-CoV-2 seropositive adults aged 18–55 years. Forty participants were enrolled across two cohorts: a low-dose cohort receiving 140 μg OMV/70 μg Spike (OMV + Spike, n = 13; OMV alone, n= 3; Placebo, n = 5) and a high-dose cohort receiving 280 μg of OMV/140 μg of Spike (OMV + Spike, n = 13; OMV alone, n = 3; Placebo, n = 3), administered on Days 1 and 22. Safety was assessed through adverse events, vital signs, laboratory parameters, ECG, and pulse oximetry. Immunogenicity was evaluated via systemic SARS-CoV-2 neutralizing antibodies, antigen-specific antibodies (IgG and IgA), and mucosal antibodies (IgA in nasal wash). Results: Intranasal administration of OMVs combined with SARS-CoV-2 Spike protein was safe, well-tolerated, and immunogenic. No serious adverse events were reported, and adverse events were predominantly mild and transient. Dose-dependent increases in systemic and mucosal immune responses were observed, with statistically significant enhanced serum IgG and nasal wash IgA antibodies in the high-dose group. Conclusions: The current clinical data confirm key aspects of the preclinical profile, which demonstrate the potential of the Nm-nOMV platform as a strong adjuvant for mucosal vaccines. These findings support the broader application of the Nm-nOMV vaccine platform in pandemic preparedness. Full article

Non-invasive drug delivery for ocular diseases remains a significant challenge in ophthalmology, as conventional eye drops offer less than 5% bioavailability due to pre-corneal barriers and the corneal epithelium. This review explores the intranasal (IN) route as a promising strategy for targeting both the anterior and posterior segments of the eye. The IN route leverages several distinct pathways: the nasolacrimal reflex for remote physiological stimulation; the “neural bridge” through the cribriform plate, allowing direct perineural and vascular transport via the olfactory and trigeminal nerves to bypass the blood–retinal barrier; and systemic absorption that avoids hepatic first-pass metabolism. Pre-clinical evidence indicates that IN administration of agents such as erythropoietin, nerve growth factor, and insulin achieves superior retinal concentrations compared to topical or systemic dosing, offering neuroprotection in models of retinal degeneration and glaucoma. Clinically, varenicline nasal spray is already FDA-approved for dry eye disease, while intranasal steroids demonstrate a favorable ocular safety profile without significantly increasing intraocular pressure. Although limited by mucociliary clearance and small delivery volumes, the IN route offers a painless, non-invasive alternative to intraocular injections, potentially enhancing patient compliance. Future advancements in mucoadhesive nanocarriers are essential to optimize drug residence time and realize the full potential of nose-to-eye delivery in chronic ophthalmic care. Full article

Background: Effective strategies for delivering neuroprotective agents to the brain remain a major challenge due to the poor solubility, rapid metabolism, and low bioavailability of promising molecules, such as 7,8-dihydroxyflavone (7,8-DHF). This small-molecule TrkB receptor agonist exhibits significant antioxidant, neuroprotective properties, and additional effects on metabolic regulation, but its therapeutic potential is limited by unfavorable pharmacokinetic characteristics. Nanotechnology-based delivery systems are increasingly explored to improve drug stability, enhance bioavailability, and facilitate direct nose-to-brain transport following intranasal administration. In this study, lipid nanoparticles encapsulating 7,8-DHF were developed using a fish-oil-based lipid core enriched with ω-3 polyunsaturated fatty acids (DHA and EPA) and naturally derived excipients, including soybean lecithin and ε-polylysine. Methods: The formulation was optimized using a Design of Experiments (DoE) approach based on a 2³ full factorial design, evaluating drug concentration, lecithin concentration, and surfactant type (Pluronic^® F127 or Tween^® 80). The main formulation responses considered were particle size, polydispersity index (PDI), zeta potential, and encapsulation efficiency. Results: The optimized nanoparticles exhibited nanometric dimensions (<250 nm); spherical morphology, confirmed by TEM; low polydispersity (PDI < 0.3); and adequate encapsulation efficiency. Stability studies in simulated biological fluids indicated good physicochemical stability for up to 48 h, while interaction studies with mucin suggested a good interaction within the mucus environment. ROS scavenging capacity was confirmed through the DPPH chemical assay, and in vitro experiments on olfactory ensheathing cells, selected as a biologically relevant model for their anatomical localization along the olfactory pathway, showed reduced cytotoxicity of the encapsulated drug compared with the free form. Conclusions: Collectively, these results support the potential application of the developed nanoformulation in the intranasal delivery of 7,8-DHF. Full article

This study aimed to determine whether intranasal hinokitiol modulates short-term salivary secretory IgA (SIgA) secretion dynamics and IgA antibody-forming cell (AFC) activity in the submandibular glands of aged mice, a model of age-associated mucosal immune decline. Aged BALB/c mice received intranasal hinokitiol (50 μg) once weekly for 4 weeks. Saliva was collected on days 0, 7, 14, and 21 at baseline, 0.5 h, 1.5 h, 3 h, and 6 h after each administration. SIgA levels were measured using an enzyme-linked immunosorbent assay. On day 21, IgA AFCs were enumerated using an enzyme-linked immunosorbent spot assay, and their viability and proliferative activity were assessed using the MTT assay. Salivary SIgA rose transiently after each dose, peaking at 1.5 h and returning to baseline by 6 h. By day 21, baseline SIgA secretion was significantly higher than at day 0, indicating a cumulative effect. IgA AFCs were unchanged in number, but viability and proliferation increased at 0.5 and 1.5 h, coinciding with SIgA peaks. Flow cytometry revealed significant expansion of B220⁺CD38⁺ memory B-cells; B220⁺CD138⁺ plasma cells were unaffected. Intranasal hinokitiol transiently enhances salivary SIgA secretion in aged mice, likely through short-term modulation of salivary gland immune activity. This non-invasive approach may aid mucosal defense in aging populations. These findings suggest that intranasal HNK may represent a novel non-invasive approach for enhancing mucosal immune function during aging and may provide a basis for future preventive strategies against oral and respiratory infections. Full article

Extensive efforts have been undertaken by numerous researchers to control respiratory viruses across the domains of diagnosis, prevention, and treatment. In this study, we developed a niclosamide–polysaccharide nasal spray (NPNS) formulation based on xanthan gum (XG), a naturally derived polysaccharide, and niclosamide, a conventional anthelmintic agent. We then evaluated its therapeutic efficacy following intranasal administration under influenza virus-infected conditions. NPNS was assessed for cytotoxicity under Good Laboratory Practice (GLP) conditions in accordance with ISO 10993-5, and no cytotoxic effects were observed. In influenza virus-infected human nasal epithelial cells (HNEc), NPNS treatment resulted in at least 92.5% suppression of viral gene expression. Furthermore, NPNS demonstrated significantly greater antiviral activity compared to Placebo 1 and Placebo 2, which were formulated by excluding niclosamide and XG, respectively. Owing to the physicochemical properties conferred by XG, NPNS exhibited prolonged retention on the nasal mucosa in a mouse model. Consistently, NPNS showed potent antiviral efficacy in influenza-infected mice. In addition, NPNS treatment was associated with the downregulation of S-phase kinase-associated protein 2 (SKP2), a host factor known to facilitate intracellular viral replication. Collectively, these findings suggest that NPNS may serve as a first-line protective barrier during the early stage of influenza infection by simultaneously blocking viral entry and suppressing viral replication through its dual physicochemical and molecular mechanisms. Full article

Background/Objectives: The recent approval of the first intranasal calcitonin gene-related peptide receptor antagonist (CGRP-RA), zavegepant, has increased the relevance of this drug class in treating acute migraine. However, introducing an alternative delivery method may result in a different real-world safety profile. Thus, the aim of this study was to assess adverse events (AEs) related to zavegepant through a retrospective pharmacovigilance disproportionality analysis. Methods: We analyzed Individual Case Safety Reports (ICSRs) presenting zavegepant as the suspected drug, submitted to the Food and Drug Administration (FDA) Adverse Event Monitoring System (AEMS) database between 1 January 2023 and 31 December 2025. ICSRs were assessed by using descriptive and disproportionality analyses. Reporting odds ratios (RORs) with 95% confidence intervals (CIs) were used as disproportionality measures. Results were deemed significant if the ROR 95% CI lower bound was >1 and ≥3 ICSRs were available for each drug–event pair. Results: A total of 509 zavegepant-related ICSRs were identified. Most ICSRs involved female patients (n = 353; 69.4%), with a median (quartile 1, Q1–quartile 3, Q3) age of 45 (34–56) years. The Medical Dictionary for Regulatory Activities (MedDRA^®) Preferred Terms with the highest RORs were nasal discomfort (n = 62; ROR = 298.85; 95%CI [228.91, 390.17]), rhinalgia (10; 126.09; [67.34, 236.09]), dysgeusia (147; 94.72; [78.19, 114.75]), pharyngeal ulceration (3; 79.20; [25.42, 246.75]), and upper-airway cough syndrome (16; 62.87; [38.19, 103.49]). Conclusions: These results suggest a safety profile for zavegepant consistent with previous knowledge regarding CGRP-RAs. However, nasal and/or oropharyngeal AEs, plausibly related to intranasal exposure, may affect perceived tolerability and timely use, warranting further investigation. Full article

Larixyl acetate, a primary component of Larch turpentine, is a naturally occurring compound with a broad spectrum of medicinal properties, including anti-inflammatory effects. It is a potent and selective inhibitor of TRPC6, a widely expressed Ca²⁺ channel that is involved in many respiratory diseases. Despite its demonstrated efficacy, it lacks a well-defined preclinical and phenotypic safety profile, which limits its therapeutic potential and implementation. In this study, female BALB/c mice were used to assess the toxicity of intranasally administered Larixyl acetate through a subacute model based on OECD Test Guideline 412, followed by a detailed analysis of physical, blood, biochemical, and tissue changes at the administration sites and beyond. Within the study’s 30-day timeframe, our results show no statistically significant differences (p > 0.05) in any of the examined toxicity parameters between the controls or three treatment groups (0.5, 1, and 2 mg/kg). While no pharmacokinetic data were obtained to confirm local or systemic exposure of Larixyl acetate, these findings are crucial for establishing a solid foundation for future therapeutic endeavors, especially in the context of TRPC6-driven respiratory diseases. Full article

Background/Objectives: The recreational use of fentanyl (FT) combined with xylazine (XZ), known as “tranq-dope,” poses a growing public health threat due to its high toxicity and mortality. This study evaluated the effectiveness of naloxone (NX), its lipophilic prodrug NX90, and their combinations with the mixed κ-agonist/µ-antagonist nalbuphine (NB) in reversing overdose and restoring respiratory function in a rat model. Methods: Male and female Wistar rats received intramuscular FT (0.104 mg/kg) + XZ (1 mg/kg) to induce overdose, followed by intranasal administration of NX, NX90, or combinations with NB. Physiological parameters, reflex recovery, time to overdose, and reversal outcomes were assessed during individualized clinical monitoring. Results: At the low FT dose (0.052 mg/kg), adding XZ (1 mg/kg) shortened time to overdose by ~2600 s compared with FT alone, whereas onset times were similar at medium and high FT doses. In the dose-finding cohort, FT + XZ co-administration was associated with a higher respiratory rate than FT alone at the highest fentanyl dose tested, an exploratory finding warranting confirmation in larger studies. Most interventions did not significantly shorten time to reversal; however, NX + NB (females) and NX90 + NB (both sexes) showed shorter reversal times than NX alone. However, respiratory rate at reversal was significantly improved with NX + NB, ½NX90 + NB and NX90 + NB (90 ± 6, 86 ± 5 and 92 ± 5 breaths/min) compared with naloxone alone (80 ± 6 breaths/min). Interventions containing nalbuphine (κ-agonist/µ-antagonist) yielded higher RR and HR at reversal than NX alone, consistent with an interpretive framework in which κ–µ opioid balance may influence observed physiological recovery patterns. Conclusions: Comparable or improved reversal outcomes could be achieved using half-doses of NX or NX90 with NB—potentially reducing the total dose of naloxone and mitigating the risk of precipitated withdrawal in individuals with opioid use disorder. Full article

Background/Objectives: Insomnia severely impairs quality of life. Oral melatonin (MEL) suffers from poor brain delivery. Intranasal administration bypasses the blood–brain barrier, but rapid mucociliary clearance shortens drug retention, and MEL poor water solubility limits its nasal dissolution. Traditional in situ gels have “gelation-first, spreading-second” defects, causing uneven distribution. Herein, we developed a two-step sequential ion-triggered in situ gel combined with MEL liposomes (MEL-Lips-Gel) to enhance solubility, achieve instant uniform coating, and prolong retention for efficient nose-to-brain delivery. Methods: MEL-Lips were dispersed in alginate (first component) and calcium gluconate served as the second component. After sequential spray, the two components mix and form an ion-crosslinked gel. Rheology, in vivo fluorescence imaging, in vitro release, open-field/sucrose preference tests, and H&E staining were performed. Results: MEL-Lips showed uniform size and good encapsulation. The sequential system achieved instant widespread spreading and rapid gelation, significantly prolonged nasal retention, enabled sustained brain delivery, and reversed insomnia-induced hyperactivity and anxiety-like behaviors more effectively than oral MEL, intranasal MEL solution, liposomes alone, or non-liposomal gel, with good nasal safety. Conclusions: This sequential ion-triggered liposome-in-gel strategy synergistically overcomes rapid clearance (via gel) and poor solubility (via liposomes), enhancing nose-to-brain delivery of melatonin and providing a promising platform for insomnia therapy. Full article

Objectives: This study aimed to investigate the therapeutic effects and potential mechanisms of Lonicerae japonicae Flos (Jinyinhua, JYH) against respiratory syncytial virus (RSV)-induced pneumonia by integrating lung tissue metabolomics with gut microbiota analysis. Methods: An RSV-infected mouse model was established through intranasal inoculation. Lung pathological changes, viral RNA levels, lung index, and inflammatory cytokine levels were evaluated. Untargeted metabolomics and 16S rRNA gene amplicon sequencing were performed to characterize JYH-mediated alterations in pulmonary metabolites and the gut microbiota. Spearman correlation analysis was conducted to assess associations between differentially abundant bacterial genera and significantly altered metabolites. Results: JYH alleviated RSV-induced pulmonary histopathological injury, reduced viral RNA levels, decreased lung index and interleukin-6 (IL-6) levels, and increased interferon-γ (IFN-γ) levels. Metabolomic profiling identified 46 differential metabolites, among which 26 showed a reversal trend following JYH administration. These metabolites were mainly enriched in pathways associated with the synaptic vesicle cycle, lysosomal function, and Forkhead box O (FoxO) signaling. Gut microbiota analysis showed that JYH increased microbial richness and diversity, whereas KEGG-based functional prediction indicated that the differentially abundant taxa were primarily involved in amino acid, carbohydrate, and nucleotide metabolism. Moreover, correlation analysis revealed significant associations between key bacterial genera, including Gemella, Sutterella, and CC_115, and differential metabolites such as pyridoxamine, uridine monophosphate (UMP), and argininosuccinic acid. Conclusions: JYH may protect against RSV-induced pneumonia by restoring pulmonary metabolic homeostasis and modulating gut microbiota composition. These findings provide new insights into metabolite–microbiota interactions underlying the anti-RSV activity of JYH. Full article

Vaccination represents the cornerstone of Newcastle disease control. Nanotechnology offers a promising approach to improve the effectiveness of DNA vaccines, supporting their use as an alternative to conventional platforms. Herein, the Avian Orthoavulavirus 1 (AOAV-1) fusion (F) gene was cloned into a DNA expression plasmid (pDNA). After validating the constructed pDNA-F and confirming robust intracellular protein expression in vitro, three polymeric nanoparticles (NPs)-based formulations were generated using Chitosan (Cs), poly(lactic-co-glycolic) (PLGA), and poly(amidoamine) (PAMAM)-Dendrimers. Physicochemical characterization, stability assessment, and in vitro release analysis confirmed nanoparticle formation and effective DNA incorporation. In vivo experiments were conducted to comparatively evaluate the immunogenicity, particularly the immune priming capacity, and protective efficacy of nanoparticle-based formulations and naked pDNA-F, all tested in parallel at standardized pDNA doses via intranasal (IN) and intramuscular routes. PAMAM-Dendrimers-pDNA-F IM group demonstrated superior efficacy, with 100% survival, the highest post-challenge anamnestic antibody titers, and a pronounced reduction in viral RNA shedding. PLGA-NPs-pDNA-F IN group demonstrated enhanced efficacy, with 90% survival. Naked pDNA-F surpassed the Cs-NPs-pDNA-F in both immune priming and clinical protection, with Cs-NPs-pDNA-F exhibiting the lowest overall performance. These findings highlight that DNA vaccine performance depends on both carrier type and administration route, with PAMAM dendrimers and PLGA enhancing efficacy, whereas chitosan demonstrated reduced efficacy under the tested conditions. Full article

Influenza A virus (IAV) remains a major global health threat despite available vaccines and antiviral agents, while current therapies are limited by drug resistance and safety concerns. Curcuminoids exhibit antiviral and anti-inflammatory activities but are constrained by poor water solubility and low bioavailability. To address these limitations, we investigated the antiviral and immunomodulatory properties of a water-solubilized curcuminoid nanoparticle formulation (C–S/M) in both in vitro and in vivo models of IAV infection. To evaluate the potential antiviral and anti-inflammatory effects of C–S/M, we performed a cytopathic effect (CPE) reduction assay in triplicate at 0.001 MOI and quantitative real-time PCR (qRT-PCR) targeting viral NS1 transcripts in MDCK cells. C–S/M suppressed viral NS1 vRNA levels in MDCK cells at lower curcuminoid-equivalent concentrations than native curcuminoids and attenuated IAV-induced TNF-α, IL-6, and IL-8 production. Furthermore, in vivo antiviral efficacy was evaluated in female C57BL/6 mice intranasally infected with IAV and treated orally with C–S/M. Survival, lung viral loads, pulmonary cytokine levels, and splenic immune cell phenotypes were analyzed. In IAV-infected mice, oral administration of C–S/M modestly improved survival and significantly reduced lung viral burden and pulmonary proinflammatory cytokine levels. In addition, in vivo C–S/M treatment was associated with recovery of virus-suppressed T-cell immune responses, including increased Th1 and activated CD8⁺ T cells, reduced regulatory T-cell expansion, and restoration of multifunctional CD4⁺ and CD8⁺ T cells. These findings suggest that C–S/M exerts antiviral and immunomodulatory effects in experimental IAV infection and may serve as a potential adjunctive candidate for further investigation against influenza-associated inflammation. Full article

Neuromuscular and neurodegenerative (NMND) disorders are diseases that cause progressive damage to the central nervous system leaving patients with symptoms that negatively affect everyday living with death almost inevitable. These include amyotrophic lateral sclerosis (ALS), Lewy body dementia (LBD), and Parkinson’s disease (PD) with cases expected to increase in the future. Intranasally administered stem cell-derived exosomes/secretome have been seen as potential therapeutic options for these disorders in preclinical animal models. This study sought to observe the efficacy of mesenchymal stem cell-derived exosomes/secretome in patients with ALS, LBD, and PD. Based off these preclinical studies, we conducted a case-controlled series experiment with 86 patients with ALS, LBD, or PD, with the independent variable being the treatment and the dependent variable being the clinical response. These patients were recruited and given intranasal instillations of various MSC-derived exosome/secretome products. Subsequent treatments were given to patients who did not have a response to one product. Patients were followed up at one week, one, two, three, and six months post-treatment. Historical external controls were used for comparison to clinical outcomes. There were no serious adverse events in any patient. A total of 67 of 86 (77%) patients showed a positive clinical response to at least one product. Outcomes were strongly associated with greater treatment frequency for ALS and LBD. Intranasal administration of MSC-derived exosome/secretome products were safe, and most patients showed overall improvement with at least one product. Some patients also saw a substantial decrease in the rate of decline compared to historical controls. These results also give rise to the hypothesis: do MSC-derived exosomes/secretome treatments show efficacy in other NMND disorders? The primary limitation of this study is the 6-month follow-up. Full article

Background: Baicalein (BA) is a poorly soluble flavonoid with limited oral bioavailability. This study aimed to enhance the solubility and nasal absorption of the compound using a dual-carrier system that combines cyclodextrin inclusion complexes and thermosensitive hydrogels. Methods: The inclusion complexes of BA with hydroxypropyl-β-cyclodextrin (HP-β-CD) or sulfobutyl-β-cyclodextrin (SBE-β-CD), namely BA-HP-β-CD and BA-SBE-β-CD, were prepared via solution stirring and characterized by solubility, dissolution, scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), thermogravimetric analysis-differential scanning calorimetry (TG-DSC), and Madin-Darby canine kidney (MDCK) cell permeation. The optimal complexes were incorporated into chitosan/β-glycerophosphate thermosensitive hydrogels (BA/HP-Gel and BA/SBE-Gel), followed by evaluations of gelation properties, in vitro release, and in vivo pharmacokinetics in rats. Results: The water solubility of BA-HP-β-CD and BA-SBE-β-CD increased 572 and 582 times, with MDCK permeability enhanced by 5.3 and 2.9 times, respectively. Both hydrogels showed rapid solution-gel transition at nasal temperature and sustained release. Following intranasal administration, BA/HP-Gel and BA/SBE-Gel achieved relative bioavailabilities of 623.5% and 697.8%, respectively, compared with BA-Gel. Conclusions: The dual-carrier platform effectively improved BA solubility, permeability, and nasal bioavailability, offering a promising strategy for nasal delivery of poorly soluble drugs. Full article

Trauma-related autobiographical memories can manifest as involuntary, vivid, emotionally charged intrusions that perpetuate avoidance, negative emotions, and functional impairment. While these memories are central to post-traumatic stress disorder (PTSD), they also occur across diagnoses and are often reported in depressive disorders, including treatment-resistant depression (TRD). Although trauma-focused psychotherapies are effective, their routine implementation can be limited by dropout, residual symptoms, and difficulty engaging patients with severe depression, dissociation, or complex comorbidities. Intranasal esketamine is an approved rapid-acting treatment for TRD and has been hypothesized to create transient conditions that may facilitate psychotherapeutic work on traumatic memories. This narrative review synthesizes clinical and translational evidence on ketamine and esketamine for PTSD and trauma-related symptoms, with particular attention to the distinction between intravenous ketamine studies, intranasal esketamine data, and studies combining these compounds with psychotherapy. Currently, the most robust evidence in this area comes from three randomised trials of intravenous ketamine for PTSD. In contrast, data on intranasal esketamine and psychotherapy-combination approaches are mainly from pilot studies, retrospective analyses, or case reports. We additionally propose a pragmatic, feasibility-oriented protocol integrating intranasal esketamine with a structured traumatic-memory intervention for TRD patients with clinically relevant trauma-memory symptoms. The novelty of the proposal does not lie in claiming efficacy, but in specifying a standardised imagery rescripting module and predefining two timing hypotheses. The proposal targets patients with TRD with relevant trauma-memory symptoms, and it embeds the intervention within existing esketamine-care infrastructure. Overall, the available literature supports mechanistic plausibility and preliminary feasibility more than clinical efficacy. The evidence base remains small, heterogeneous, and largely uncontrolled, and controlled studies are needed before efficacy claims can be made. Full article