“Schizophrenia is a chronic and complex psychiatric disorder characterized by profound disturbances in perception, cognition, emotion, and behavior. The disorder manifests through positive symptoms (hallucinations, delusions, disorganized thinking), negative symptoms (reduced emotional expression, avolition, social withdrawal), and cognitive impairments including executive dysfunction and working memory deficits. (Steen et al., 2006; van Os and Kapur, 2009) According to the World Health Organization's most recent estimates, schizophrenia affects approximately 24 million people worldwide, representing about 0.32% of the global population (1 in 300 people) (Luvsannyam et al., 2022; Charlson et al., 2018). The lifetime prevalence ranges from 0.3% to 0.7% across different populations (Charlson et al., 2018; Solmi et al., 2023; Davis et al., 2022), with significant geographical, socioeconomic, and demographic variations. As a leading cause of disability globally, schizophrenia imposes substantial burdens on affected individuals, their families, and healthcare systems, with estimated annual costs exceeding $155 billion in the United States alone (Davis et al., 2022).”

The exact etiology of schizophrenia remains incompletely understood, but current evidence suggests a multifactorial origin involving genetic predisposition, neurochemical imbalances, and environmental influences (van Os and Kapur, 2009; Sawa and Snyder, 2003). The dopamine hypothesis has long dominated pathophysiological models, proposing that hyperactivity of dopaminergic signaling, particularly in the mesolimbic pathway, underlies positive symptoms such as hallucinations and delusions (van Os and Kapur, 2009). This theory is supported by the efficacy of dopamine D₂ receptor antagonists (e.g., phenothiazines) in reducing psychotic symptoms and the observation that dopamine-enhancing drugs like amphetamines can produce schizophrenia-like symptoms (van Os and Kapur, 2009; Sawa and Snyder, 2003; Lang et al., 2007). However, the introduction of atypical antipsychotics affecting both dopamine and serotonin pathways indicates a more complex neurochemical landscape involving multiple neurotransmitter systems and intricate receptor interactions (van Os and Kapur, 2009).

Beyond the dopamine hypothesis, the glutamate hypothesis has gained substantial attention as an explanatory framework for schizophrenia pathophysiology (Luvsannyam et al., 2022; McCutcheon et al., 2020). This hypothesis proposes that hypofunction of the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors contributes to positive, negative, and cognitive symptoms. Evidence includes postmortem brain studies and neuroimaging research demonstrating reduced glutamate transmission and decreased NMDA receptor density in patients with schizophrenia (Luvsannyam et al., 2022; McCutcheon et al., 2020). Administration of NMDA receptor antagonists such as ketamine and phencyclidine (PCP) produces a spectrum of schizophrenia-like symptoms in healthy individuals, including hallucinations, delusions, and cognitive deficits, supporting the centrality of glutamatergic dysfunction in the disorder's neurochemistry (Luvsannyam et al., 2022; McCutcheon et al., 2020).

Beyond classical neurotransmitter systems, emerging evidence implicates neuropeptide dysregulation in schizophrenia pathophysiology. The oxytocin system has garnered particular attention, with studies demonstrating reduced oxytocin levels in cerebrospinal fluid of patients with schizophrenia (Rubin et al., 2010; Beckmann et al., 1985). Oxytocin receptor polymorphisms have been associated with negative symptom severity and social cognition deficits (Montag et al., 2013). Similarly, vasopressin system abnormalities contribute to cognitive impairments and emotional dysregulation characteristic of the disorder (Beckmann et al., 1985). Substance P and neurotensin alterations have been documented in postmortem brain tissue from schizophrenia patients, suggesting their involvement in symptom manifestation (Sharma et al., 1997). These findings highlight the potential for neuropeptide-based therapeutic interventions to address symptoms inadequately treated by dopamine-focused antipsychotics. However, clinical application of neuropeptides faces substantial challenges including enzymatic degradation, poor BBB penetration, and rapid systemic clearance, necessitating advanced delivery technologies such as polymeric nanoparticle systems (Fortuna et al., 2014; Mittal et al., 2014; Erdő et al., 2018).

Structural brain abnormalities have been extensively documented in individuals with schizophrenia through advanced neuroimaging techniques (Velligan and Rao, 2023; Smigielski et al., 2020). Research consistently demonstrates reduced total brain volume, enlarged lateral and third ventricles, and decreased volumes in critical regions including the hippocampus and prefrontal cortex (Smigielski et al., 2020; Howes et al., 2023). These structural alterations are thought to contribute to the diverse cognitive and functional impairments associated with the disorder (Howes et al., 2023). Modern imaging modalities including magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), and positron emission tomography (PET) have been instrumental in identifying these abnormalities (Zhu et al., 2024; Alemán-Gómez et al., 2023). Collectively, these findings support a neurodevelopmental conceptualization of schizophrenia and provide valuable biomarkers for monitoring disease progression and treatment response (Zhu et al., 2024; Alemán-Gómez et al., 2023; Townsend et al., 2023).

From a functional perspective, individuals with schizophrenia exhibit notable alterations in cerebral blood flow and glucose metabolism, particularly in brain regions associated with cognition and emotional regulation such as the prefrontal cortex and parahippocampal gyrus. Functional neuroimaging studies have identified these metabolic changes, which likely contribute to the core cognitive deficits and thought disorganization characteristic of the disorder. Disrupted blood flow and metabolism in these regions may impair synaptic transmission and neuronal connectivity, thereby exacerbating the functional impairments typical of schizophrenia (Townsend et al., 2023).

The increasing number of global regulatory approvals and marketed products utilizing nasal dosage forms demonstrates that the intranasal (IN) route is gaining recognition as a valuable alternative to parenteral administration, particularly in emergency situations, while offering greater convenience than oral delivery. Intranasal formulations provide rapid drug delivery, ease of administration, and the potential for direct nose-to-brain transport, which is especially beneficial for central nervous system (CNS) disorders (Fortuna et al., 2022; Sonvico et al., 2023). Current applications span diverse therapeutic areas, including nasal decongestion (Afrin®), smoking cessation (Nicotrol®), acute pain relief (NARCAN®), migraine treatment (ZAVZPRET™), prostate cancer, endometriosis, flu prevention (FluMist Quadrivalent®), opioid dependence (Advaspray®), and acute anxiety episodes (VALTOCO®). Additionally, researchers are actively investigating intranasal delivery for emerging infectious diseases such as COVID-19, with several vaccine candidates and therapeutic agents currently undergoing clinical evaluation. This expanding range of applications underscores the versatility and potential of the intranasal route for both systemic and CNS-targeted drug delivery. Table 1 presents representative marketed intranasal drug products approved worldwide (Fortuna et al., 2022; Sonvico et al., 2023; Vitore et al., 2023; Mi et al., 2024; Sonvico et al., 2018).

Current treatment strategies for schizophrenia primarily rely on antipsychotic medications (APMs), categorized as first-generation (typical) and second-generation (atypical) antipsychotics (McCutcheon et al., 2020; Stępnicki et al., 2018; Zorkina et al., 2020; Raghav et al., 2023). Atypical antipsychotics are more frequently prescribed due to their improved side effect profiles (McCutcheon et al., 2020; Stępnicki et al., 2018). While both classes demonstrate efficacy in managing acute psychotic episodes and reducing relapse risk, significant treatment challenges persist including limited effectiveness in addressing negative symptoms and cognitive deficits, high relapse rates upon treatment discontinuation, and diverse adverse effects such as extrapyramidal symptoms, metabolic complications (weight gain, dyslipidemia, insulin resistance), sedation, and cardiovascular concerns (Zorkina et al., 2020; Raghav et al., 2023). These limitations underscore the urgent need for innovative drug delivery approaches and novel formulation strategies that can enhance therapeutic efficacy while minimizing adverse effects and improving patient adherence.

Furthermore, schizophrenia management typically requires lifelong pharmacotherapy, presenting considerable challenges to treatment adherence and patient quality of life (Markowicz-Piasecka et al., 2023). Although oral administration of antipsychotics remains the most common approach due to convenience and cost-effectiveness, it suffers from limitations including low bioavailability due to first-pass hepatic metabolism, enzymatic degradation in the gastrointestinal tract, and increased propensity for systemic adverse effects, all of which compromise therapeutic effectiveness (Markowicz-Piasecka et al., 2023). Conversely, parenteral administration, particularly long-acting injectable (LAI) formulations, offers improved bioavailability and enhanced adherence by reducing dosing frequency (Markowicz-Piasecka et al., 2023). However, this route is invasive, typically requires clinical supervision, and generally incurs higher costs, potentially deterring patient acceptance (Markowicz-Piasecka et al., 2023). These challenges highlight the need for innovative non-invasive delivery modalities that improve CNS targeting, enhance patient compliance, and reduce systemic adverse effect exposure.

In both oral and parenteral administration, effective brain delivery of antipsychotic medications confronts substantial obstacles posed by the blood-brain barrier (BBB) (Pardridge, 2005a; Singh et al., 2025a). This highly selective protective interface restricts the passage of over 98% of small-molecule drugs and nearly all large-molecule therapeutics into the CNS (Pardridge, 2005a; Singh et al., 2025a). The BBB comprises tightly connected endothelial cells, active efflux transporters, and metabolic enzymes that collectively limit drug penetration (Gandhi et al., 2024a; Terstappen et al., 2021; Jiao et al., 2024a). Small, lipophilic molecules with molecular weights below approximately 400–600 Da can traverse the BBB via passive diffusion, but larger or hydrophilic compounds typically require innovative delivery strategies to achieve therapeutically effective brain concentrations (Gandhi et al., 2024a; Terstappen et al., 2021; Jiao et al., 2024a).

Given these challenges, intranasal (IN) drug delivery has garnered increasing attention as a non-invasive and promising alternative for treating CNS disorders (Fortuna et al., 2014; Illum, 2003). The nasal cavity provides direct access to the brain through olfactory and trigeminal neural pathways, circumventing the BBB and enabling rapid therapeutic onset (Fortuna et al., 2014; Pardridge, 2005a; Illum, 2003). The mechanisms underlying nose-to-brain (NtB) transport are illustrated in Table 2 and Fig. 1, which depict the principal anatomical routes facilitating drug transport from nasal mucosa to brain tissues. (Pardridge, 2005b; Singh et al., 2025b)

The intranasal route bypasses first-pass hepatic metabolism and gastrointestinal degradation while improving patient compliance through non-invasive, convenient self-administration without professional supervision (Fortuna et al., 2014; Illum, 2003). However, despite these advantages, IN delivery faces several challenges including limited dose volume (typically restricted to 100–150 μL per nostril), enzymatic degradation by nasal mucosal enzymes, rapid mucociliary clearance, and substantial inter-individual variability in nasal physiology. Additionally, formulation considerations such as maintaining isotonicity, pH compatibility, and optimal viscosity are critical to ensure adequate mucosal retention and minimize irritation (Illum, 2003; Gandhi et al., 2024b; Wu et al., 2023a; Yu et al., 2016).

The blood-brain barrier poses a formidable challenge even for systemically absorbed intranasally delivered therapeutics. The BBB consists of tightly connected endothelial cells with minimal pinocytotic activity, active efflux transporters (P-glycoprotein, BCRP, MRP family), and metabolic enzymes that collectively restrict most drugs from achieving therapeutically effective CNS concentrations (Gandhi et al., 2024b; Wu et al., 2023a; Jiao et al., 2024b). Fig. 2 illustrates the principal barriers drugs encounter in the nasal cavity before reaching cerebral tissues.

In recent years, nanotechnology has emerged as a promising strategy to overcome the limitations of conventional brain drug delivery approaches (Elmowafy et al., 2023; Awad et al., 2023; Kendre et al., 2023). Among the various nanocarrier systems investigated, polymeric nanoparticles (PNPs) have demonstrated particular efficacy in enhancing the stability, bioavailability, and brain-targeting efficiency of antipsychotic medications (APMs) administered via the intranasal route. PNPs protect encapsulated drugs from enzymatic degradation, prolong nasal residence time, facilitate partial circumvention of the blood– brain barrier (BBB), and enable controlled and sustained drug release profiles (Elmowafy et al., 2023; Awad et al., 2023; Kendre et al., 2023). Furthermore, nanoparticle surfaces can be rationally engineered through ligand conjugation or polymer modification to improve targeting specificity and promote neuronal uptake (Barbu et al., 2009; Singh et al., 2015; Shen et al., 2016).

This review critically examines the potential of intranasal antipsychotic delivery, with a specific focus on PNP-mediated nose-to-brain (NtB) transport. By integrating physiological, pharmacokinetic, and formulation perspectives, the review highlights key challenges associated with conventional delivery routes and discusses how emerging nasal nanocarrier systems address these limitations. Multiple formulation strategies have been explored to enhance nasal drug retention and brain exposure, including permeation and absorption enhancers, cell-penetrating peptides, mucoadhesive and mucus-penetrating agents, enzyme inhibitors, hydrogel-based systems, and nanoparticle drug delivery systems (NDDS), either individually or in combination (Pandey et al., 2022). Among these, nanoparticle-based platforms have shown particular success in overcoming the physical and biological barriers of the nasal mucosa, enabling efficient drug accumulation in brain tissue while minimizing systemic exposure (Pandey et al., 2022).

Driven by the need for safer and more effective therapies for central nervous system (CNS) disorders, the pharmaceutical field has increasingly focused on advanced drug delivery technologies and alternative administration routes capable of bypassing physiological brain barriers (Pandey et al., 2022; Bahadur et al., 2020; Misra and Pathak, 2023; Ferreira et al., 2023a; Maher et al., 2023; Rai et al., 2023; Shikalgar et al., 2024). In this context, the intranasal route has gained considerable attention as a non-invasive and patient-friendly approach for direct brain targeting, with the potential to enhance therapeutic efficacy and adherence. Consequently, innovation in schizophrenia treatment is no longer limited to the discovery of new active pharmaceutical ingredients but increasingly relies on formulation-driven solutions that improve brain delivery, reduce systemic adverse effects, and optimize pharmacokinetic performance.