Trifluoperazine (TFP) is an oral antipsychotic agent used to treat depression, agitation, anxiety, schizophrenia, and other psychotic disorders [1]. However, its oral administration is associated with extensive presystemic metabolism, resulting in low bioavailability and the need for frequent high dosing to maintain therapeutic plasma levels [2]. Several strategies have been explored to enhance TFP delivery, including buccal and rectal administration [3,4] as well as oral dispersible tablets or bilayer floating tablets [5,6].

Intranasal delivery has emerged as a promising alternative, as it bypasses hepatic metabolism and provides dual advantages: rapid systemic absorption via the nasal mucosa and direct nose-to-brain transport through the olfactory pathway, avoiding the blood–brain barrier. Nonetheless, TFP’s physicochemical properties—such as high water solubility and ionization at physiological pH—may limit its passive permeation across the lipophilic nasal epithelium [6]. To address this, nanocarrier systems have been proposed to improve permeability and retention in the nasal cavity [7,8].

Leciplex is a cationic nanocarrier that may improve the permeation of drugs through the nasal membrane by electrostatic interaction between the positively charged group of leciplex and the negatively charged sialic acid moieties found on the mucosal surface of the nasal epithelium [9]. Leciplex offers advantages compared to conventional vesicular systems due to its simpler synthesis process and composition, which includes phospholipid, a cationic surfactant, and a biocompatible solvent [10].

Although nasal delivery bypasses first-pass metabolism and allows direct brain targeting, it is hindered by rapid mucociliary clearance, short residence time, and variable absorption [11]. Mucoadhesive thermosensitive organogels address these drawbacks by undergoing sol-to-gel transition at physiological temperature, ensuring ease of administration with in situ gelation that prolongs retention and reduces drainage [12]. The addition of mucoadhesive polymers, such as carbopol, further enhances contact with the nasal mucosa, while the organogel matrix can stabilize nanocarriers and provide controlled release [13]. These properties make organogels particularly suitable for nose-to-brain delivery, where sustained availability at the absorption site is critical.

To further improve delivery and targeting, superparamagnetic iron oxide nanoparticles (SPIONs) have attracted attention. SPIONs are biocompatible, surface-modifiable particles of magnetite (Fe3O4), maghemite (γ-Fe2O3), or hematite (α-Fe2O3) that exhibit magnetism only under an external magnetic field [14,15]. This property enables remote, site-specific control of drug localization. SPION-based systems have been successfully applied to enhance drug-loaded nanocarrier delivery across biological barriers, including ocular [16] and brain-targeted applications [17,18]. In particular, applying an external magnet has been shown to improve the nose-to-brain targeting of resveratrol-loaded SPION bilosomes [15] and the transport of magnetic transferrin liposomes across the blood–brain barrier [16].

To the best of our knowledge, no previous study has systematically compared the role of SPIONs in enhancing intranasal systemic absorption versus promoting direct nose-to-brain olfactory targeting. While SPION-assisted approaches have been explored for improving brain delivery of various drugs, the distinction between magnet placement on the nose versus the brain has not yet been investigated. This gap underlines the novelty of the present work, which evaluates how external magnet location can be used as a tunable strategy to control drug distribution and therapeutic efficacy. We hypothesized that when the magnet is placed on the nose, the magnetic force primarily enhances nanoparticle retention at the nasal mucosa, thereby favoring systemic absorption through the rich vasculature of the nasal cavity. In contrast, when the magnet is positioned over the brain region, the field gradient promotes the movement of superparamagnetic nanoparticles along the olfactory pathway toward the olfactory bulb, thereby facilitating direct nose-to-brain transport.

Therefore, the present study was designed to develop and evaluate a SPION-loaded trifluoperazine leciplex thermosensitive mucoadhesive organogel for intranasal delivery. with the emphasis on evaluating the effect of external magnet placement—on the nose to improve systemic absorption or on the brain to promote olfactory-mediated targeting—on pharmacokinetic and pharmacodynamic outcomes.