Dual-Functional Amine-Modified Aluminum-Doped MCM-41 Nanoparticles for Concurrent Zoledronic Acid Adsorption and Geranylgeraniol Delivery for Prevention of Medication-Related Osteonecrosis of the Jaw

This study aimed to develop a bifunctional nanomaterial that could simultaneously adsorb zoledronic acid (ZA) and release geranylgeraniol (GGOH) to reverse ZA-induced cytotoxicity. The synthesized aluminum-doped mesoporous silica nanomaterial (AM) was subsequently amine-functionalized by 3-aminopropyltriethoxysilane, generating both amine- and aluminum-containing nanomaterial (NAM), to enhance the ability of nanoparticles to adsorb GGOH. The comprehensive characterization results confirmed the successful aluminum-doping and amine-functionalization of the nanoparticles. The results acquired from both thermogravimetric analysis and high-performance liquid chromatography demonstrated that NAM, rather than AM, served as a good nanocarrier for GGOH loading and controlled-releasing. NAM exhibited up to 12.48% GGOH loading efficiency and GGOH sustained release for over 10 days with a release profile best fitted by the Higuchi model (<i>R</i> ² = 0.9868), indicating a diffusion-controlled mechanism. Although AM demonstrated much higher ZA adsorption (>95%), NAM still retained moderate ZA adsorption (∼30%). In vitro assays using RAW 264.7 murine cells revealed that GGOH-loaded NAM was noncytotoxic and completely reversed ZA-induced cytotoxicity and metabolic impairment. Furthermore, it displayed negligible hemolytic activity (<0.5%). The combination of targeted drug delivery and bisphosphonate sequestration via nanostructured silica nanocarriers presents a promising therapeutic approach with translational potential in the prevention of medication-related osteonecrosis of the jaw. The promising cellular results, serving as a preclinical foundation, provide a stepping stone toward in vivo applications.