Cholecalciferol-grafted hollow mesoporous silica nanoparticles for targeted and sustained caffeine delivery in alopecia therapy

Alopecia is a common and often distressing condition marked by progressive hair loss and follicular damage. While finasteride and minoxidil (MNX) remain standard treatments for alopecia, their adverse systemic effects drive the need for safer alternatives. Caffeine (Caf), a natural stimulant with hair growth–promoting properties, is limited by its hydrophilicity and poor follicular retention. To address these limitations, we developed hollow mesoporous silica nanoparticles (HMSNs) grafted with cholecalciferol (VitD-HMSNs) to improve targeted delivery and sustained release of Caf. The high lipophilicity of cholecalciferol enhances follicular permeation, and its antioxidant and anti-inflammatory effects may act synergistically with Caf to promote localized hair-regrowth while reducing systemic exposure. HMSNs were synthesized via Sol-Gel and Template-Assisted methods, followed by selective etching. The nanoparticles showed suitable physicochemical properties for transdermal delivery, including an average particle size of ∼150 nm, a pore size of 2.8 nm, and a specific surface area of 1095 m²/g. Fourier-transform infrared (FT-IR) spectroscopy confirmed successful cholecalciferol grafting. Caf was efficiently loaded (% encapsulation efficiency, 32.11 %; % loading capacity, 24.31 %), and in vitro release demonstrated a more sustained profile for caffeine-loaded hollow mesoporous silica nanoparticles grafted with cholecalciferol (VitD-Caf@HMSNs) than for ungrafted HMSNs. Franz diffusion studies showed enhanced skin permeation with VitD-Caf@HMSNs (476.63 μg/cm²). Confocal laser scanning microscopy (CLSM) imaging confirmed deeper nanoparticle penetration—up to 280 μm into porcine skin—along with accumulation around hair follicles, supporting the system's targeting potential. In human hair follicle dermal papilla cells (HFDPCs), MTT assays confirmed the biocompatibility of VitD-Caf@HMSNs. In dihydrotestosterone (DHT)-challenged cells, VitD-Caf@HMSNs markedly reduced reactive oxygen species (ROS), achieving antioxidant activity comparable to that of MNX. In summary, these findings indicate that VitD-Caf@HMSNs are a receptor-targeted, biocompatible nanocarrier that enables sustained, localized Caf delivery for alopecia therapy, potentially offering a minimally invasive alternative to conventional treatments.