Repair and regeneration of damaged neurons is a promising therapeutic strategy for central nervous system (CNS) diseases such as ischemic stroke (IS). However, achieving efficient neuronal repair and regeneration after CNS injury through noninvasive methods remains a significant challenge. Therefore, this study proposes, for the first time, an ultrasonic nasal drop formulation that induces efficient regeneration of damaged neurons through electropharmacological coupling in an noninvasive manner. Liposomes containing the natural anti-inflammatory drug Timosaponin B-II (TB) were coated onto barium titanate nanoparticles (BTO) to form LTO@TB. Using microfluidic technology and a Schiff base reaction, LTO@TB was encapsulated into aldehyde-based and methacrylate-modified microspheres (MS) to create the ultrasonic nasal drop MS@LTO@TB. The aldehyde groups of MS@LTO@TB spontaneously formed amide bonds with the numerous amino groups in the nasal mucosa, facilitating specific adhesion. Due to its enhanced bioadhesion and efficient transmembrane transport, LTO@TB was continuously and noninvasively delivered to the brain when administered nasally. Additionally, under ultrasonic stimulation, LTO@TB in the brain exerted an electropharmacological coupling effect, achieving noninvasive electrical stimulation of damaged neurons. MS@LTO@TB modulated microglial phenotypes, restored electrical signal conduction among damaged neurons, reshaped the inflammatory microenvironment, reduced neuronal apoptosis, activated the PI3K/AKT signaling pathway, and promoted axonal regeneration. MS@LTO@TB also showed the unique ability to alleviate inflammation and promote neuronal remodeling in a mouse model of middle cerebral artery occlusion/reperfusion (MCAO/R). This study presents a promising strategy involving the nasal administration of ultrasonic nasal drops as a noninvasive and efficient treatment for CNS injuries.

Glioma, a primary malignant tumor of the central nervous system, remains a formidable challenge despite advancements in treatment. Immunotherapies hold promise, but their efficacy is hindered by the blood-brain barrier (BBB) and immunosuppressive tumor microenvironment (TME). The nose-to-brain transport pathway offers a potential solution for bypassing the BBB and avoiding systemic absorption issues. In this study, we developed a calcium phosphate (CaP)-covered nanovaccine (NV) based on hepatitis B core antigen derived virus-like particles (HBc VLPs), optimized for mucosal delivery applications. After biomineralization, this NVs exhibited enhanced mucosal adhesion and significantly higher accumulation in glioma tissue. Furthermore, by leveraging the immunogenicity of HBc VLPs and displaying a glioma-associated antigen EphA2671-679 on its surface, this NVs served as both immunogen and adjuvant. They promoted significant antiglioma therapeutic efficacy and elicited robust, durable tumor suppression by increasing effective T cell infiltration, reducing regulatory T cells and M2-type tumor-associated macrophages. This innovative NV construction strategy highlights the potential of CaP-coated VLPs for enhancing nose-to-brain delivery and immunological enhancement, offering a promising avenue for the development of effective immunotherapies for glioma.

Intracerebral hemorrhage (ICH) remains a life-threatening condition due to its high mortality and limited treatment options. This study explores a novel therapeutic strategy using engineered exosomes derived from endothelial progenitor cells (EPC-EXOs) to improve ICH outcomes. EPC-EXOs were modified with a CD47-enriched red blood cell membrane via co-extrusion to enhance their anti-phagocytic properties, thereby reducing degradation by activated microglia after ICH. A minimally invasive endoscopic-guided delivery system was developed to facilitate the targeted intranasal administration of these engineered EPC-EXOs (m-Oe-EXOs), allowing direct entry into brain tissue. We confirmed m-Oe-EXOs' high retention and effective distribution in the brain. Functional analysis demonstrated that EPC-EXOs significantly promoted the proliferation, migration, and angiogenesis of brain microvascular endothelial cells (BMECs), with proteomic analysis identifying HSP90 as a key protein activating the Akt pathway in BMECs. In vivo, m-Oe-EXOs demonstrated therapeutic efficacy by improving blood-brain barrier integrity, reducing hematoma volume, and enhancing neurological recovery in ICH rats. Collectively, our findings highlight the potential of minimally invasive, endoscopic-guided delivery of m-Oe-EXOs as an innovative approach for ICH treatment, providing new insights into targeted, exosomes-based regenerative therapies.

Intranasal drug delivery via nanocarriers has long been a research focus for enhancing drug concentration in the brain. However, the strategy of exploiting blood-brain barrier (BBB) alterations in atherosclerotic mouse models to enhance nanoparticle-mediated delivery of bromocriptine to the hypothalamus for the treatment of prolactinomas with hyperprolactinemia has not yet been reported. This study reveals that in patients with prolactinomas complicated by arteriosclerosis, bromocriptine therapy more effectively attenuates postoperative elevations in prolactin levels. In a mouse model, liposome-encapsulated bromocriptine efficiently traversed the nasal mucosa and entered the intracranial space. Compared with normal mice, bromocriptine-loaded liposomes delivered higher bromocriptine concentrations to the hypothalamus. Single-cell RNA sequencing revealed a significant upregulation of organic anion-transporting polypeptide 1a4 (Oatp1a4) expression in the brain endothelial cells of atherosclerotic mice. Importantly, bromocriptine-loaded liposomes more effectively reduced prolactin levels in a mouse model of prolactinoma with concurrent atherosclerosis. This study provides a theoretical foundation for the precision treatment of prolactinomas in arteriosclerosis.

In the world, over 50 million people are living with Alzheimer's disease (AD), and in thirty years, this number is expected to double or even exceed that. AD is a form of dementia characterized by memory loss, language difficulties, and impaired thinking skills. It involves the accumulation of beta-amyloid plaques and tau tangles in the brain, leading to neurodegeneration and disrupted neuron communication. After diagnosis, patients typically survive for four to eight years, though some may live up to 20 years. Currently, there is no cure, and the available treatment options are limited in improving the quality of patients' lives. However, a promising perspective for treatment based on nanotechnology narrows down the possibility of personalized treatment. In this review, we explore several topics related to Alzheimer's disease to provide a comprehensive understanding of how nanotechnology can enhance treatment approaches. We examine various types of nano treatments and delivery methods, as well as the challenges they face and their associated benefits. Additionally, we highlight current nano treatments in development and discuss improved cell and animal models that can effectively test these treatments for patient safety. We also address sex differences in the pathophysiology of Alzheimer's disease, which may allow for more targeted treatment strategies. By considering these factors in conjunction, we move closer to realizing personalized medicine, ultimately improving the quality of life for patients. Nano treatments offer the potential for more specific, safer, and effective solutions in managing Alzheimer's disease.

Macromolecular Drugs (including monoclonal antibodies, recombinant proteins, and nucleic acid therapies) have become a cornerstone strategy for intervening in complex pathological mechanisms such as cancer, autoimmune diseases, and genetic disorders due to their high specificity for disease targets and low off-target toxicity. However, compared to traditional small-molecule drugs, the high molecular weight (>10 kDa) and structural complexity of macromolecular drugs result in extremely low transmembrane permeability. This is particularly challenging in the treatment of central nervous system (CNS) diseases, where the blood-brain barrier (BBB) imposes stringent selectivity, further limiting drug delivery efficiency. This review focuses on the breakthrough strategy of nose-to-brain (NtB) drug delivery. On one hand, the NtB pathway bypasses the BBB, enabling direct CNS drug delivery. On the other hand, nanocarrier technology can synergistically achieve systemic delivery and brain-targeted transport. Based on the latest research advances, this article systematically examines the feasibility of delivering macromolecular drugs via NtB administration. We comprehensively summarize relevant delivery carriers and discuss the potential advantages of intranasal-brain delivery for CNS disease treatment. Notably, while significant progress has been made in this field, further exploration is still needed regarding the mechanisms of NtB delivery and challenges in clinical translation.

Nasal drug administration constitutes an efficient and non-invasive modality of drug delivery, and its distinctive physiological structure offers potentialities for treating a variety of diseases. To elevate the drug absorption and delivery efficiency, it is of paramount importance to delineate the transport routes and their enhancement mechanisms. Nevertheless, drug absorption pathways vary depending on the disease target, these variations present opportunities for targeted delivery and challenges for achieving precision. Hence, this review outlines the anatomical structure of the nasal cavity, and subsequently elaborates on the drug transport pathways within the nasal cavity and their influencing factors. Based on the distinct sites of drug action, diseases suitable for nasal drug administration are categorized into three types: systemic diseases, local nasal diseases, and central nervous system diseases. Grounded on multiple transport routes and their influencing factors, this review proposes strategies like optimizing formulation viscosity, using penetration enhancers, adding mucosal adhesives and improving delivery device, offering insights into future advancements in nasal drug delivery systems.

Current treatment of depression is hindered by the delayed onset of the action of antidepressant drugs, often resulting in treatment failure. Therefore, new therapeutic solutions are imperative.

Venlafaxine-loaded poly(lactic-co-glycolic acid) nanoparticles were produced by a double emulsion-solvent evaporation method. Cellular safety assessment and internalization assays were carried out in vitro in human olfactory neuroepithelium cells. The antidepressant effect of intranasal (nose-to-brain) nanoparticle administration was assessed in animals submitted to an animal model of depression by behavioral tests, including open-field, sucrose preference test and tail suspension test.

The drug entrapment efficiency (55-65 %), particle size (190-210 nm), polydispersity index (<0.2), and zeta potential (-20 mV) of Venlafaxine-loaded poly(lactic-co-glycolic acid) nanoparticles were determined to be adequate. Nanoparticles did not show cytotoxic effects. Cell viability was more than 90 % for all formulations and concentrations assayed. The results of the quantitative and qualitative cell uptake assays were consistent, showing an evident internalization of the nanoparticles into the cells. Furthermore, venlafaxine-loaded nanoparticles administered for just 7 days were able to reverse the phenotype induced by a depressive-like model, showing a significant antidepressant-like effect compared to those treated with free venlafaxine.

These findings indicated that intranasal venlafaxine-loaded poly(lactic-coglycolic acid) nanoparticles could become a viable technique for improving venlafaxine brain uptake via nose-to-brain. It could also be a promising nanoplatform for enhancing the treatment of depression.

Lipid nanoparticles (LNPs) have emerged as a transformative platform for the targeted delivery of therapeutic agents, revolutionizing treatment paradigms across a spectrum of diseases. Since the inception of liposomes in the 1960s, lipid-based nanotechnology has evolved to address limitations such as poor bioavailability, off-target effects, and instability, thereby enhancing the efficacy and safety of drug administration. This review highlights the latest advancements in LNPs technology, focusing on their application in cancer therapy, gene therapy, infectious disease management, glaucoma, and other clinical areas. Recent studies underscore the potential of LNPs to deliver messenger RNA (mRNA) and small interfering RNA (siRNA) for precise genetic intervention, exemplified by breakthroughs in RNA interference and CRISPR-Cas9 genome editing. Additionally, LNPs have been successfully employed to ameliorate conditions, demonstrating their versatility in addressing both acute and chronic disorders. However, challenges persist concerning large-scale manufacturing, long-term stability, and comprehensive safety evaluations. Future research must focus on optimizing formulations, exploring synergistic combinations with existing therapies, and expanding the scope of treatable diseases. The integration of LNPs into personalized medicine and the exploration of applications in other diseases represent promising avenues for further investigation. LNPs are poised to play an increasingly central role in the development of next-generation therapeutics.

Circadian rhythms and their involvement with various human diseases, including neurological disorders, have become an intense area of research for the development of new pharmacological treatments. The location of the circadian clock machinery in the central nervous system makes it challenging to reach molecular targets at therapeutic concentrations. In addition, a timely administration of the therapeutic agents is necessary to efficiently modulate the circadian clock. Thus, the use of nanoparticles in circadian clock dysfunctions may accelerate their clinical translation by addressing these two key challenges: enhancing brain penetration and/or enabling their formulation in chronodelivery systems. This review describes the implications of the circadian clock in neurological pathologies, reviews potential molecular targets and their modulators and suggests how the use of nanoparticle-based formulations could improve their clinical success. Finally, the potential integration of nanoparticles into chronopharmaceutical drug delivery systems will be described.

The incidence of brain disorders has gained worldwide attention and the presence of the blood-brain barrier prevents numerous drugs from reaching the targeted brain. The specific physiology of the nasal cavity and the brain provides the feasibility of direct nose-brain delivery, a system that bypasses the blood-brain barrier in a non-invasive manner for brain-targeted drug delivery via intracellular and extracellular mechanisms. The use of CPPs provides further feasibility for naso-brain drug delivery studies, and liposomes, nanopolymer particles, and gels modified with CPPs have demonstrated significant brain-targeting capabilities after nasal delivery. In this paper, the physiology of the nasal cavity and brain, the pathways of naso-brain delivery and the influencing factors are discussed in detail. At the same time, the introduction, classification, mechanism of action and application of CPPs in the nasal-brain delivery system are discussed in detail to provide a theoretical basis for the in-depth study of the application of CPPs in the nasal-brain delivery system.

Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) can traverse the blood-brain barrier due to their small size. This characteristic makes them a research hotspot for the treatment of Parkinson's disease (PD) and is expected to be a potentially revolutionary strategy for treating PD. Despite this, no summary of clinical trial results has been reported.

To assess the efficacy and durability of MSC-EVs in treating PD.

Systematic searches were conducted in four electronic databases until June 2024 to collect studies on the use of MSC-EVs for this purpose. Thirteen relevant randomized controlled trials, encompassing 16 experiments, were selected for inclusion.

Behavioral assessments, including the rotarod and apomorphine turning behavior tests, indicated improvements in motor coordination (P < 0.00001); the Pole test and the Wire-hang test showed enhanced limb motor agility and synchronization (P = 0.003 and P < 0.00001, respectively). Histopathologically, there was a reduction in inflammatory markers such as tumor necrosis factor-α and interleukin-6 (P = 0.03 and P = 0.01, respectively) and an increase in tyrosine hydroxylase-positive cells in the lesion areas (P < 0.00001).

MSC-EV therapy for PD is a gradual process, with significant improvements observable more than 2 weeks after administration and lasting at least 8 weeks. This study is the first to demonstrate the efficacy and durability of MSC-EV treatment in PD.

In recent decades, nose-to-brain drug delivery has shown effectiveness in treating many central nervous system diseases. Intranasally administered drugs can be delivered to the brain through the olfactory and trigeminal pathways that bypass the blood-brain barrier. However, nose-to-brain drug delivery is challenging due to the inadequate nasal mucosa absorption of drugs and the short retention time of the intranasal formulations. These problems can be minimized through the use of nano-drug delivery systems, such as micelles, polymeric nanoparticles, nanoemulsions, liposomes, solid lipid nanoparticles, and nanostructured lipid carriers. They can enhance the drug's bioavailability in the brain via increases in drug solubility, permeation, and stability. Nose-to-brain nano-drug delivery systems have been evaluated in vivo by a number of research groups. This review aims to provide an overview of nose-to-brain delivery and recent advances in the development of nano-drug delivery systems for delivering drugs from the nose to the brain to improve the treatment of some central nervous system diseases.

In this study, spray-dried formulations differing in morphology (spherical and wrinkled), surface polarity (hydrophilic and hydrophobic), and size (20-30 µm and 3 µm) were evaluated in a nasal cast to assess their deposition profiles. The objective was to identify how formulation properties and application aspects influence the deposition profile. For this purpose, the formulations were administered at different application angles (45° and 60°), fill weights (20 mg and 40 mg), and airflow rates (0 L/min and 15 L/min) in conjunction with a UDS powder device. The results indicate a more posterior deposition profile for 45° compared to 60° due to increased deposition in the turbinate region; conversely, deposition profiles between fill weights were comparable. Application with simultaneous airflow should be avoided because of an increasing postnasal fraction. No influence of morphology could be observed, but for the surface polarity an influence was apparent, if the powder was applied with a simulated inspiration. In these cases, a hydrophobic formulation was better dispersible than a hydrophilic formulation, which led to an increased postnasal fraction. A particle size for pulmonary application demonstrated comparable results to nasal formulations with respect to the turbinate deposition but exhibited a high postnasal fraction for hydrophobic formulations.

The delivery of drugs directly from the nose to the brain has been explored for the treatment of neurological diseases, such as glioblastoma, by overcoming the blood-brain barrier. Nanocarriers have demonstrated outstanding ability to enhance drug bioavailability in the brain, following intranasal administration. However, the performance of these nanosystems may be hindered by inadequate interactions with the nasal mucosa, limiting their effectiveness in reaching the olfactory region, and consequently, the translocation of particles to the brain. Here, we designed hybrid lipid-polymer nanoparticles (LPNP), containing the cationic lipid DOTAP and the triblock copolymer Pluronic® F127 to combine the mucoadhesiveness and mucus-penetrating properties. Perillyl alcohol (POH), a molecule currently under clinical trials against glioblastoma, via intranasal route, was entrapped in the nanoparticles. LPNP-POH exhibited a balanced profile of mucus adhesion and penetration, suggesting that the formulation may enhance mucosal retention while maintaining effective mucus diffusivity. In vivo evaluations displayed higher translocation of LPNP-POH from the nasal cavity to the brain. LPNP-POH resulted in a 2.5-fold increase in the concentration of perillyl acid (a primary metabolite of POH) in the cerebral tissue compared to the free drug. In vitro assays demonstrated that LPNP-POH increased the cytotoxicity and reduced the tumor growth of U87MG glioma cells. These results highlighted that the engineered formulation, with optimized mucoadhesiveness and mucus penetration properties, improved nose-to-brain delivery of POH, offering a promising potential for glioblastoma therapy.

Upper respiratory tract infections are among the most prevalent respiratory diseases, imposing both financial and physical burdens on affected individuals. Roxithromycin (ROX), a primary drug for treating bacterial-induced respiratory tract infections, is typically administered orally due to its hydrophobic nature. However, the non-specific distribution resulting from oral administration reduces bioavailability and can cause side effects such as diarrhea.

In this study, we prepared a thermo-sensitive in-situ gel using a facile and highly reproducible method by simply mixing two types of poloxamers with ROX.

The ROX can be well dissolved in the poloxamer matrix in amorphous state to give solution. Upon intranasal administration, the ROX solution undergoes a phase transition to form in-situ gel under body temperature. This gel remains in the nasal cavity for an extended period, releasing the drug directly to the site of infection and minimizing non-specific distribution. Pharmacokinetic experiments revealed that, compared to oral administration, the bioavailability of local nasal administration increased by 1.5 times, and the drug concentration in the local nasal cavity increased by 8 times. In contrast, concentrations in the liver and small intestine did not significantly differ from those following oral administration. In vivo antibacterial experiments also showed that the ROX in-situ gel has superior antibacterial efficacy and excellent biocompatibility.

These results suggest that the thermo-sensitive ROX in-situ gel is a promising formulation for treating bacterial upper respiratory tract infections.

Traditional drug therapies suffer from problems such as easy drug degradation, side effects, and treatment resistance. Traditional disease diagnosis also suffers from high error rates and late diagnosis. Extracellular vesicles (EVs) are nanoscale spherical lipid bilayer vesicles secreted by cells that carry various biologically active components and are integral to intercellular communication. EVs can be found in different body fluids and may reflect the state of the parental cells, making them ideal noninvasive biomarkers for disease-specific diagnosis. The multifaceted characteristics of EVs render them optimal candidates for drug delivery vehicles, with evidence suggesting their efficacy in the treatment of various ailments. However, poor stability and easy degradation of natural EVs have affected their applications. To solve the problems of poor stability and easy degradation of natural EVs, they can be engineered and modified to obtain more stable and multifunctional EVs. In this study, we review the shortcomings of traditional drug delivery methods and describe how to modify EVs to form engineered EVs to improve their utilization. An innovative stimulus-responsive drug delivery system for EVs has also been proposed. We also summarize the current applications and research status of EVs in the diagnosis and treatment of different systemic diseases, and look forward to future research directions, providing research ideas for scholars.

Epilepsy is a common neurological disease characterized by distinct pathological changes in the epileptogenic zone. Antiseizure drugs (ASDs) are widely used as the primary treatment for epilepsy. To improve the efficiency of ASDs medication, stimuli-responsive nanoscale drug delivery systems (nanoDDSs), triggered by either endogenous or exogenous factors, have been developed and been considered as a noninvasive and spatial-temporal approach to epilepsy theranostics. In this review, we introduce the pathological variations observed in epileptic lesions such as dysregulated neurotransmitter systems, disrupted ion homeostasis, and dynamic inflammatory cytokine networks. Furthermore, we summarize the recent advances in functional nano-assemblies that could be activated by endogenous stimuli of pathological alterations or exogenous stimuli such as electricity, light, and other interventions. Finally, we discuss the remaining challenges and prospect the insight into perspective of future development in this field. In summary, this review aims to highlight the potential of stimuli-responsive nanoDDSs as precise, controllable and efficient strategies for addressing unresolved issues in epilepsy theranostics. STATEMENT OF SIGNIFICANCE: This review summarizes recent progress in pathological changes such as dysregulated neurotransmitter system, disrupted ion homeostasis and dynamic inflammatory cytokine network, and emphasizes endogenous/exogenous stimuli-responsive nanoscale platforms including neurotransmitter-, ion-, and other stimuli-responsive nanoDDSs, providing the prospects of smart nanoDDSs applications and discussing the challenges to offer generalized guideline for further development of epilepsy theranostics.

Glioblastoma multiforme (GBM) is considered to be one of the most devastating brain tumors with a shorter life expectancy. Several factors contribute to the dismal prognosis of GBM patients including the complicated nature of GBM, the ability of tumor cells to resist treatment, and the difficulty of delivering drugs to the brain because of barriers like the blood-brain barrier (BBB) and blood-tumor barrier (BTB). The unique challenges posed by the BBB in delivering therapeutic agents to the brain have led to the development of innovative nanotechnology-based approaches. By exploiting the olfactory/trigeminal pathway, nanosystems offer a promising strategy for targeted drug delivery to the brain, glioblastoma tumors in particular. This review contemplates varied nanocarriers, including polymeric nanoparticles, lipid-based nanosystems, in situ gel formulations, peptide, and stem cell-based nanoformulations, signifying their utility in brain targeting with minimal systemic side effects. Emerging trends in gene therapy and immunotherapy in the context of GBM treatment have also been discussed. Since safety is a paramount aspect for any drug product to get approved, this review also delves into toxicological considerations associated with intranasal delivery of nanosystems. Regulatory aspects and critical factors for the successful development of intranasal products are also explored in this review. Overall, this review underscores the significant advancements in nanotechnology for nose-to-brain delivery and its potential impact on GBM management.

Manufacturing bioactive materials for drug delivery involves developing materials that interact with biological tissues to release drugs in a controlled and targeted manner. The goal is to optimize therapeutic efficacy and reduce side effects by combining knowledge from materials engineering, biology, and pharmacology. This study presents a detailed bibliometric analysis, exploring the keywords "manufacturing," "bioactive materials," and "drug delivery" to identify and highlight significant advancements in the field. From the Web of Science, 36,504 articles were analyzed, with 171 selected for a deeper analysis, identifying key journals, countries, institutions, and authors. The results highlight the field's interdisciplinary nature, with keywords grouped into four main themes, including regenerative medicine, scaffolds, three-dimensional (3D) printing, bioactive glass, and tissue engineering. Future research in this area will focus on more effective and precise systems using technologies like 3D printing and nanotechnology to enhance the customization and control of drug release, aiming for more efficient and targeted therapies.

This paper aimed to investigate the role of surface modification on the potential interaction between CdTe quantum dots (QDs) and ABC transporters in doxorubicin-resistant lung cancer (A549/DOX) cells. For this purpose, CdTe QDs modified with -glutathione (GSH), -carboxy (COOH), and -amino (NH2) were applied, with the former two QDs exhibiting negative potentials and the latter ones being positive. All the three QDs reduced cell viability in a concentration-dependent manner, with NH2-CdTe QDs being more toxic. Such phenomena might be due to the adherence of NH2-CdTe QDs to negative cell membrane and thereby causing an enhanced accumulation. Addition of transporter inhibitors significantly enhanced the intracellular accumulation and toxicity of negative QDs, but such phenomena were barely found or even reversed for NH2-CdTe QDs, indicating that ABC transporters mainly excreted negative QDs. All the QDs caused little effects on the mRNA expression of ABC transporters, which should be due to the fact that the induction effects of QDs have been attenuated by the disruption of cell membrane. Overall, these results reveal the mechanism by which ABC transporters are involved in the efflux of CdTe QDs with different surface modifications, which could help the detoxification of QDs in the environment.

Intranasal drug delivery route has emerged as a promising non-invasive method of administering drugs directly to the brain, bypassing the blood-brain barrier (BBB) and blood-cerebrospinal fluid barriers (BCSF). BBB and BCSF prevent many therapeutic molecules from entering the brain. Intranasal drug delivery can transport drugs from the nasal mucosa to the brain, to treat a variety of Central nervous system (CNS) diseases. Intranasal drug delivery provides advantages over invasive drug delivery techniques such as intrathecal or intraparenchymal which can cause infection. Many strategies, including nanocarriers liposomes, solid-lipid NPs, nano-emulsion, nanostructured lipid carriers, dendrimers, exosomes, metal NPs, nano micelles, and quantum dots, are effective in nose-to-brain drug transport. However, the biggest obstacles to the nose-to-brain delivery of drugs include mucociliary clearance, poor drug retention, enzymatic degradation, poor permeability, bioavailability, and naso-mucosal toxicity. The current review aims to compile current approaches for drug delivery to the CNS via the nose, focusing on nanotherapeutics and nasal devices. Along with a brief overview of the related pathways or mechanisms, it also covers the advantages of nasal drug delivery as a potential method of drug administration. It also offers several possibilities to improve drug penetration across the nasal barrier. This article overviews various in-vitro, ex-vivo, and in-vivo techniques to assess drug transport from the nasal epithelium into the brain.

Epilepsy is a highly prevalent neurological disease and valproic acid (VPA) is used as a first-line chronic treatment. However, this drug has poor oral bioavailability, which requires the administration of high doses, resulting in adverse effects. Alternative routes of VPA administration have therefore been investigated, such as the nose-to-brain route, which allows the drug to be transported directly from the nasal cavity to the brain. Here, the use of nanostructured lipid carriers (NLC) to encapsulate drugs administered in the nasal cavity has proved advantageous. The aim of this work was to optimise a mucoadhesive formulation of VPA-loaded NLC for intranasal administration to improve the treatment of epilepsy. The Design of Experiment (DoE) was used to optimise the formulation, starting with component optimisation using Mixture Design (MD), followed by optimisation of the manufacturing process parameters using Central Composite Design (CCD). The optimised VPA-loaded NLC had a particle size of 76.1 ± 2.8 nm, a polydispersity index of 0.190 ± 0.027, a zeta potential of 28.1 ± 2.0 mV and an encapsulation efficiency of 85.4 ± 0.8%. The in vitro release study showed VPA release from the NLC of 50 % after 6 h and 100 % after 24 h. The in vitro biocompatibility experiments in various cell lines have shown that the optimised VPA-loaded NLC formulation is safe up to 75 µg/mL, in neuronal (SH-SY5Y), nasal (RPMI 2650) and hepatic (HepG2) cells. Finally, the interaction of the optimised VPA-loaded NLC formulation with nasal mucus was investigated and mucoadhesive properties were observed. The results of this study suggest that the use of intranasal VPA-loaded NLC may be a promising alternative to promote VPA targeting to the brain, thereby improving bioavailability and minimising adverse effects.

Nimodipine is the primary clinical drug used to treat cerebral vasospasm following subarachnoid hemorrhage. Currently, tablets have low bioavailability when taken orally, and injections contain ethanol. Therefore, we investigated a new method of nimodipine administration, namely, nasoencephalic administration. Nasal administration of nimodipine was carried out by attaching the cell-penetrating peptide octa-arginine (R8) to liposomes of nimodipine and incorporating it into a temperature-sensitive in situ gel. The prepared liposomes and gels underwent separate evaluations for in vitro characterization. In vitro release exhibited a significant slow-release effect. In vitro toad maxillary cilia model, RPMI 2650 cytotoxicity, and in vivo SD rat pathological histotoxicity experiments showed that all the dosage from the groups had no significant toxicity to toad maxillary cilia, RPMI 2650 cells, and SD rat tissues and organs, and the cilia continued to oscillate up to 694 ± 10.15 min, with the survival rate of the cells being above 85%. A transwell nasal mucosa cell model and an isolated porcine nasal mucosa model were established, and the results showed that the osmolality of the R8-modified nimodipine liposomal gel to nasal mucosal cells and isolated porcine nasal mucosa was 30.41 ± 2.14 and 65.9 ± 7.34 μg/mL, respectively, which was significantly higher than that of the NM-Solution and PEGylated nimodipine liposome gel groups. Animal fluorescence imaging studies revealed that the R8-modified nimodipine liposomal gel displayed increased brain fluorescence intensity compared to the normal liposomal gel. Pharmacokinetic results showed that after transnasal administration, the AUC(0-∞) of the R8-modified nimodipine liposomal gel was 11.662 ± 1.97 μg·mL-1, which was significantly higher than that of the plain nimodipine liposomal gel (5.499 ± 2.89 μg·mL-1). Brain-targeting experiments showed that the brain-targeting efficiencies of the PEGylated nimodipine liposome gel and R8-modified PEGylated nimodipine liposome gels were 20.44 and 33.45, respectively, suggesting that R8/PEG/Lip-NM-TSG significantly increased the brain-targeting of the drug.

Major depressive disorder (MDD) is a prevalent mental disorder that significantly impacts social and psychological function, but no effective medication is currently available. Circular RNAs (circRNAs) have been reported to participate in the pathogenesis of MDD which are envisioned as promising therapeutic targets. However, nonviral-based delivery strategies targeting circRNA against MDD are not thoroughly investigated. Here, it is identified that circATF7IP is significantly upregulated in plasma samples and positively correlated with 24-Hamilton Depression Scale (HAMD-24) scores of MDD patients. Synergistic amine lipid nanoparticles (SALNPs) are designed to deliver siRNA targeting circATF7IP (si-circATF7IP) into the hippocampus brain region by intranasal administration. Intranasal delivery of SALNP-si-circATF7IP successfully alleviated the depressive-like behaviors in the LPS-induced mouse depression model via decreasing CD11b+CD45dim microglia population and pro-inflammatory cytokine productions (TNF-α and IL-6). These results indicate that the level of circATF7IP positively correlates with MDD pathogenesis, and SALNP delivery of si-circATF7IP via intranasal administration is an effective strategy to ameliorate LPS-induced depressive-like behaviors.

The nanodrug delivery system-based nasal spray (NDDS-NS) can bypass the blood-brain barrier and deliver drugs directly to the brain, offering unparalleled advantages in the treatment of central nervous system (CNS) diseases. However, the current design of NNDS-NS is excessively focused on mucosal absorption while neglecting the impact of nasal deposition on nose-to-brain drug delivery, resulting in an unsatisfactory nose-to-brain delivery efficiency. In this study, the effect of the dispersion medium viscosity on nasal drug deposition and nose-to-brain delivery in NDDS-NS was elucidated. The optimized formulation F5 (39.36 mPa·s) demonstrated significantly higher olfactory deposition fraction (ODF) of 23.58%, and a strong correlation between ODF and intracerebral drug delivery (R2 = 0.7755) was observed. Building upon this understanding, a borneol-modified lipid nanoparticle nasal spray (BLNP-NS) that combined both nasal deposition and mucosal absorption was designed for efficient nose-to-brain delivery. BLNP-NS exhibited an accelerated onset of action and enhanced brain targeting efficiency, which could be attributed to borneol modification facilitating the opening of tight junction channels. Furthermore, BLNP-NS showed superiority in a chronic migraine rat model. It not only provided rapid relief of migraine symptoms but also reversed neuroinflammation-induced hyperalgesia. The results revealed that borneol modification could induce the polarization of microglia, regulate the neuroinflammatory microenvironment, and repair the neuronal damage caused by neuroinflammation. This study highlights the impact of dispersion medium viscosity on the nose-to-brain delivery process of NDDS-NS and serves as a bridge between the formulation development and clinical transformation of NDDS-NS for the treatment of CNS diseases.

Ferulic acid (FA), a phenolic compound abundant in the cell walls of seeds, leaves, and roots of various fruits, vegetables, cereals, and grains, is renowned for its wide range of biological activities, including antioxidant, anti-inflammatory, antimicrobial, and anticancer properties. Despite its therapeutic potential, the clinical application of FA is hindered by challenges such as poor water solubility, limited bioavailability, rapid metabolism, and instability under physiological conditions. To address these issues, nanotechnology has emerged as a transformative approach, enhancing FA's pharmacokinetic profile. Various nanoparticle-based systems, including polymer-based and lipid-based nanoparticles, have been developed to encapsulate FA. These systems have demonstrated significant improvements in FA's solubility, stability, and bioavailability, with studies showing enhanced antioxidant activity and controlled release profiles. Further, the surface engineering of these nanoparticles provides targeted drug/phytochemical delivery potential. The targeted delivery of drugs/phytochemicals significantly enhances the therapeutic efficacy and minimizes systemic side effects. This review explores the therapeutic potential of FA, the limitations in its clinical application, and the advancements in nanoparticle-based delivery systems that are paving the way for its effective therapeutic use.

Alzheimer's disease (AD) is a progressive neurodegenerative disease and apolipoprotein E (APOE) genotypes (APOE2, APOE3, and APOE4) show different AD susceptibility. Previous studies indicated that individuals carrying the APOE2 allele reduce the risk of developing AD, which may be attributed to the potential neuroprotective role of APOE2. However, the mechanisms underlying the protective effects of APOE2 is still unclear.

We analyzed single-nucleus RNA sequencing and bulk RNA sequencing data of APOE2 and APOE3 carriers from the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort. We validated the findings in SH-SY5Y cells and AD model mice by evaluating mitochondrial functions and cognitive behaviors respectively.

The pathway analysis of six major cell types revealed a strong association between APOE2 and cellular stress and energy metabolism, particularly in excitatory and inhibitory neurons, which was found to be more pronounced in the presence of beta-amyloid (Aβ). Moreover, APOE2 overexpression alleviates Aβ1-42-induced mitochondrial dysfunction and reduces the generation of reactive oxygen species in SH-SY5Y cells. These protective effects may be due to ApoE2 interacting with estrogen-related receptor alpha (ERRα). ERRα overexpression by plasmids or activation by agonist was also found to show similar mitochondrial protective effects in Aβ1-42-stimulated SH-SY5Y cells. Additionally, ERRα agonist treatment improve the cognitive performance of Aβ injected mice in both Y maze and novel object recognition tests. ERRα agonist treatment increased PSD95 expression in the cortex of agonist-treated-AD mice.

APOE2 appears to enhance neural mitochondrial function via the activation of ERRα signaling, which may be the protective effect of APOE2 to treat AD.

Many brain diseases pose serious challenges to human life. Alzheimer's Disease (AD) and Parkinson's Disease (PD) are common neurodegenerative diseases that seriously threaten human health. Glioma is a common malignant tumor. However, drugs cannot cross physiological and pathological barriers and most therapeutic drugs cannot enter the brain because of the presence of the Blood-brain Barrier (BBB) and Bloodbrain Tumor Barrier (BBTB). How to enable drugs to penetrate the BBB to enter the brain, reduce systemic toxicity, and penetrate BBTB to exert therapeutic effects has become a challenge. Nanosuspension can successfully formulate drugs that are difficult to dissolve in water and oil by using surfactants as stabilizers, which is suitable for the brain target delivery of class II and IV drugs in the Biopharmaceutical Classification System (BCS). In nanosuspension drug delivery systems, the physical properties of nanostructures have a great impact on the accumulation of drugs at the target site, such as the brain. Optimizing the physical parameters of the nanosuspension can improve the efficiency of brain drug delivery and disease treatment. Therefore, the key challenges, influencing factors, and future perspectives of nanosuspension in enhancing brain drug delivery are summarized and reviewed here. This article aims to provide a better understanding of nanosuspension formulation technology used for brain delivery and strategies used to overcome various physiological barriers.