Size-Controlled Mesoporous Silica Nanoparticles via Template Nanoarchitectonics from a Deferoxamine Derivative for Enhanced Blood–Brain Barrier Permeability and Neuroprotective Chelation Therapy

Neurodegenerative diseases (NDs) are progressive and fatal disorders that primarily affect the elderly and remain incurable. Characterized by irreversible neuronal loss, they leave patients increasingly dependent on caregivers. Despite diverse clinical presentations, NDs share common pathological features, such as protein aggregation, metal accumulation, oxidative stress, and chronic neuroinflammation. Despite numerous efforts, most therapeutic candidates fail due to poor efficacy, toxicity concerns, or limited blood–brain barrier (BBB) permeability, thereby highlighting the need for enhanced formulations. Nanomedicine offers a promising strategy to improve the therapeutic performance of existing compounds. This study presents a nanoformulation of the metal chelator deferoxamine (DFO) based on the drug-structure-directing agent (DSDA) concept, in which a hydrophobic chain is covalently linked to the DFO molecule to impart amphiphilic properties and acts as a template for the synthesis of a mesoporous silica nanoparticle (MSN). This approach allows for the one-pot fabrication of DFO-loaded MSNs (DFO@MSNs) with controlled sizes of below 20 nm without the need for surfactant removal. Compared to MCM-41-based systems, DFO@MSNs exhibited a higher drug loading capacity (10 mg of DFO/100 mg of MSNs) and a significantly more sustained release profile, minimizing premature leakage, with less than 20% of the cargo released over 24 h. Safety of DFO@MSN was assessed using BV-2 microglial and human neuroblastoma SH-SY5Y cell lines, and in vitro assays confirmed its enhanced iron-chelating capacity and effective inhibition of aluminum-induced amyloid aggregation. Furthermore, permeability studies using a Caco-2 in vitro BBB model revealed that a smaller particle size greatly enhances transport across the barrier. These results support DFO@MSNs as a promising multifunctional nanoplatform for targeted chelation therapy and neuroprotection in ND treatment.