The central nervous system (brain and spinal cord) regulates essential physiological processes from sensory processing to movement control, simultaneously preserving whole-body equilibrium (Prahlad, 2020). As the principal integrative center of the CNS, the brain maintains bidirectional communication with the external environment through complex neural networks, regulating cognition, sensory processing, and behavior. In parallel, the spinal cord functions as a critical conduit for electrochemical signal transmission, mediating afferent and efferent impulses between the brain and the peripheral nervous system (Fouad et al., 2021). In recent years, the increasing global prevalence of CNS disorders, largely driven by demographic aging, has emerged as a significant public health concern. Epidemiological data from 2021 indicate that Alzheimer's disease (AD) and related dementias constituted the second leading cause of disability-adjusted life years (DALYs) among individuals aged 60–79 years. Meanwhile, Parkinson's disease (PD) ranked as the third most burdensome condition among individuals aged 80 years and older (GBD 2021 Nervous System Disorders Collaborators, 2024). AD and PD, the most common neurodegenerative disorders associated with aging, currently impact approximately 45 million and 8 million people worldwide based on epidemiological evidence (Hou et al., 2019). Despite the growing therapeutic demand, conventional drug delivery methods such as oral and intravenous administration continue to exhibit significant limitations in CNS disease management. These limitations arise from both from medication processing issues—including liver filtration during first-pass metabolism and unintended tissue exposure and the selective filtering mechanisms of blood-brain barrier (BBB). The BBB functions as a tightly regulated physiological interface that protects the CNS from harmful substances. While essential for neural protection, this barrier creates major treatment obstacles. Studies show that more than 98 % of small-molecule drugs and almost all large biologic medications cannot reach effective levels in the brain due to BBB restrictions (Pedder et al., 2025). As a result, traditional delivery strategies often require elevated systemic dosages to achieve minimal CNS efficacy, which concomitantly increases the risk of peripheral toxicity (J. Gao et al., 2024). Although invasive methods such as intrathecal injection can improve CNS drug concentrations, their clinical application is constrained by procedural complexity and associated risks (Fowler et al., 2020). Moreover, conventional methods frequently result in uneven drug distribution within the CNS, leading to insufficient targeting of affected regions and reduced therapeutic outcomes (D. Wu et al., 2023).

Given these challenges, intranasal delivery has emerged as a promising non-invasive strategy for the administration of therapeutics targeting the CNS. This approach, particularly when combined with immunomodulatory or neuroprotective agents, has shown considerable potential in the management of neurodegenerative diseases. Its key advantages include rapid onset of action, improved bioavailability, and, importantly, the ability to circumvent the BBB by facilitating direct drug transport to the brain via the nasal–cerebral pathway, thereby enhancing therapeutic efficacy (Jeong et al., 2023). These characteristics make intranasal delivery an attractive option not only for neurodegenerative conditions but also for the treatment of acute CNS injuries and psychiatric disorders (Awad et al., 2023; Y. Zhang et al., 2023). Furthermore, the incorporation of nanotechnology into intranasal delivery systems has advanced the precision of drug targeting and therapeutic effectiveness, while concurrently reducing systemic adverse effects (Marrocco et al., 2024). Fig. 1 provides a comprehensive depiction of the global burden of neurological disorders and the historical development of intranasal delivery as a therapeutic strategy for central nervous system (CNS) diseases. A) outlines the top ten neurological conditions ranked by disability-adjusted life years (DALYs), with nervous system cancer, autism spectrum disorder, and preterm birth contributing the greatest health burdens worldwide. B) highlights key milestones in basic research, including the advancement of inhalation devices, the elucidation of intranasal delivery mechanisms, and the incorporation of nanoparticles and nebulizer in intranasal drug delivery. C) illustrates the clinical translation of these findings, tracing the progression of FDA-approved intranasal therapeutics from 1997 to 2023, alongside emerging innovations such as gene therapy, intranasal delivery of neural stem cells, and AI-guided nanorobotic drug delivery systems. Collectively, the figure underscores the increasing clinical relevance and technological advancement of intranasal delivery as a non-invasive and targeted approach for the treatment of CNS disorders. Furthermore, our review lists currently available inhalable medications for CNS disorders (Table 1), including diazepam (VALTOCOR, 1963) for seizures, esketamine (SPRAVATO, 1970) for depression, and naloxone (NARCAN, 1971) for opioid overdose. Migraine treatments include sumatriptan (TOSTRA, 1992), zolmitriptan (ZOMIG, 1997), and Onzetra Xsali (2016). Pain management options include butorphanol (STADOL NS, 2000) and fentanyl (LAZANDA, 2015). Midazolam (NAYZILAM, 2019) is used for cluster seizures, and najmefene (OPVEE, 2023) is the latest addition for opioid overdose. These formulations provide diverse therapeutic options through unique mechanisms and delivery routes (Awad et al., 2023).

Although the considerable advantages of intranasal drug delivery for the treatment of CNS disorders, significant challenges remain in formulation optimization, inhalation device engineering, and clinical translation. Formulation optimization focuses on improving drug stability and bioavailability while ensuring compatibility with the nasal mucosa. Nanocarriers have shown promise in improving CNS drug delivery by protecting therapeutic agents from enzymatic degradation and prolonging their retention in the nasal cavity (Terstappen et al., 2021). However, the design and optimization of nanocarriers require precise control of particle size, surface charge, and surface modifications to ensure that they can effectively penetrate the BBB or enter the CNS through the olfactory pathway. Therefore, future researches need to further explore the optimal design, safety evaluation, and translational potential of nanocarriers systems to overcome current barriers and enable broader clinical adoption for CNS indications (M. I. Teixeira et al., 2024).

In addition, the design of inhalation devices plays a crucial role in the effectiveness of intranasal delivery. First, the design of inhalation devices needs to ensure that the drug is delivered accurately and uniformly to specific areas of the nasal cavity to maximize drug absorption and efficacy (X. Li et al., 2024). Second, for patients with neurological conditions that impair cognitive or motor functions, user-friendly device design becomes especially critical to ensure correct and independent administration. Therefore, the portability and durability of the device are also factors to be considered to improve long-term patient compliance (A. A. D'Souza et al., 2021). Clinical translation further demands adherence to regulatory standards and comprehensive trials to demonstrate both safety and efficacy, while also addressing practical issues such as nasal irritation and inter-individual variability in absorption. Overcoming these multifaceted challenges requires a multidisciplinary and collaborative effort from drug discovery, engineering and clinical research to advance the development of intranasal delivery for CNS disorders (Huang et al., 2024).

In conclusion, intranasal drug delivery presents a novel and feasible strategy for overcoming the traditional limitations associated with central nervous system (CNS) drug administration. This review summarizes the pathophysiological mechanisms underlying common CNS disorders, evaluates the therapeutic potential of intranasal delivery, and compares its advantages with other non-invasive administration routes. Furthermore, emerging technologies—such as nanocarrier-based systems and advanced delivery devices—are discussed in detail. Finally, we examine the current progress in clinical development and commercialization, and propose strategic directions to facilitate the successful translation of intranasal delivery approaches in the treatment of neurological diseases.