Alopecia areata (AA) is a non-scarring autoimmune disorder characterized by hair loss and significant psychological burden (Tzur Bitan et al., 2022). Globally, more than 10 million individuals of all ages are affected by this condition (Hooshyar et al., 2021). The clinical presentation of AA varies widely, ranging from patches of bald areas on the scalp and beard (patchy alopecia areata) to complete scalp hair loss (alopecia totalis), and in some cases, the loss of all body hair (alopecia universalis) (Singh et al., 2024). The pathophysiology of AA involves the collapse of immune privilege in anagen-phase hair follicles (HFs), rendering them vulnerable to autoimmune attack. Genetic predisposition and dysregulated T cell responses are central to this process, wherein perifollicular CD4+ and intrafollicular CD8+ T cells infiltrate HFs, disrupting the hair cycle by prematurely inducing catagen (regression phase). Histopathological analyses corroborate these mechanisms, revealing dense lymphocytic infiltrates around anagen-phase HFs—a phenomenon absent in healthy follicles (Fernandes Melo et al., 2018, Korta et al., 2018). Current therapeutic strategies for AA include the use of immunomodulators (e.g., diphenylcyclopropenone), topical agents (e.g., minoxidil and anthralin), and phototherapy. While these modalities can stimulate transient hair regrowth, they fail to modify disease progression. Topical corticosteroids, such as clobetasol-17-propionate (CP), remain first-line treatments (off-label) due to their potent immunosuppressive and anti-inflammatory effects (Jung et al., 2017, Lenane et al., 2014, Tosti et al., 2006, Ucak et al., 2012). However, conventional CP formulations (e.g., lotions, creams, gels, and ointments) exhibit suboptimal pharmacokinetic profiles, such as low aqueous solubility, less stability, and poor absorption, which limit follicular penetration, necessitating frequent dosing that exacerbates systemic absorption and patient non-adherence (Nair et al., 2022). Chronic use also predisposes patients to local adverse effects, including skin atrophy, telangiectasia, and folliculitis (Hengge et al., 2006). These limitations underscore the need for advanced drug delivery systems that enhance targeted follicular delivery while minimizing off-target exposure.

Nanotechnology-based approaches have emerged as promising solutions to overcome these challenges. Nanocrystals (NCs)—nanosized (200–500 nm) drug crystals stabilized by surfactants or polymers—offer distinct advantages, including 100 % drug-loading capacity, enhanced solubility, and prolonged localized release (Möschwitzer and Müller, 2006, Pawar et al., 2014). Unlike conventional nanocarriers such as liposomes or nanoemulsions—which are limited by low drug payloads (due to carrier matrix dilution) and physicochemical instability (e.g., lipid oxidation and surfactant degradation)—NCs circumvent these issues by virtue of their pure drug crystalline structure. NCs achieve high drug-loading capacity and exhibit superior stability under physiological conditions. Their small size and high surface-area-to-volume ratio enable efficient follicular accumulation, as demonstrated in preclinical models. This occurs through enhanced intercellular penetration and prolonged retention within HF reservoirs, bypassing the rapid clearance seen with carrier-dependent systems (Corrias et al., 2017, Giradkar et al., 2024, Bodnár et al., 2024, Sinha et al., 2013).

CP, a highly lipophilic glucocorticoid (log P = 3.5), exhibits negligible water solubility, which limits its bioavailability in conventional topical formulations (Kumar et al., 2021). These physicochemical properties make CP an ideal candidate for NC formulation, as NCs bypass solubility challenges by converting the drug into nanosized crystalline particles. This approach enhances follicular targeting by leveraging the inherent lipophilicity of CP, which promotes partitioning into lipid-rich HF structures (Lademann et al., 2007, Patzelt et al., 2011).

While NCs have been extensively explored for diverse routes of administration—including oral, parenteral, pulmonary, and ocular delivery—due to their high drug-loading capacity (100 %) and stability (Al Shaal et al., 2010, Kesisoglou et al., 2007, Lai et al., 2013), their application for HF-targeted drug delivery remains underexplored. To the best of our knowledge, this is the first study that systematically evaluates NCs as a strategy to enhance CP delivery to HFs, the primary pathological site in AA.

In this study, a CP-NC suspension was developed using a combined (top-down and bottom-up) approach and characterized for particle size (PS), polydispersity index (PDI), zeta potential (ZP), and morphology. This CP-NC suspension was subsequently embedded in a gel matrix (CP-NC-Gel) to prolong scalp contact and stability. Comparative evaluations of viscosity, spreadability, in vitro drug release, ex vivo skin penetration, and follicular deposition were conducted against a conventional CP gel (CP-Gel).

Thus, by leveraging NC technology, the present study aims to address the critical limitations of existing AA therapies, offering a paradigm shift toward precision dermatology with enhanced efficacy and reduced adverse effects.