Mesoporous Silica Nanoparticles
Mesoporous Silica nanoparticles possess many advantages as drug delivery systems. These NPs often have large surface areas, tunable sizes and shapes, multifunctional abilities, and good hemocompatibility in various physiological environments125. Furthermore, their high drug loading capabilities and feasible surface modifications make them a promising nanotherapeutic option for AD.
In the study by Chen et al., Mesoporous Silica Nanoparticles (MSNs) were surface-conjugated with ultrasmall ceria nanocrystals (CeNCs) and iron oxide nanocrystals (IONCs) to target hyperphosphorylated tau and inhibit critical pathways of tau-driven AD pathogenesis126. The MSNs were loaded with methylene blue (MB), which is an inhibitor of tau aggregation. The nanoparticles were further functionalized with the tau tracer, T807, to optimize their selectivity and binding capabilities to tau aggregates. In vivo studies indicated that CeNC/IONC/MSN-T807 NPs have enhanced retention in the hippocampus of tauopathy rat models. Further studies demonstrated that the formulated NPs had the ability to significantly reduce mitochondrial reactive oxygen species in vitro. In addition, the synergistic effects of CeNC/IONC/MSN-T807-MB NPs resulted in effective inhibition of tau phosphorylation at the protein sites, S396, S199, S404, and T205 and the near-elimination of tau-tau binding. The CeNC/IONC/MSN-T807-MB NPs were also capable of inhibiting tau aggregation to 13.3%, while MB was capable of inhibiting tau aggregation to only 25%. The group treated with CeNC/IONC/MSN-T807-MB NPs exhibited more than 71.8% in cell viability. In contrast, the control group’s cell viability was only 23.8% and the MB group’s cell viability was 35.2%. The NPs formulated by Chen et al., reduced the neuronal apoptosis rate to 10.34%, while sole MB treatment decreased the neuronal apoptosis rate by merely 23.54%. In vivo studies confirmed that the CeNC/IONC/MSN-T807-MB NPs could preserve memory functions by reducing microglial and astrocyte activation. With further studies to increase BBB penetration capabilities, CeNC/IONC/MSN-T807-MB NPs could be clinically utilized to treat AD patients126.
Sun et al. composed Magnetic Mesoporous Silica Nanoparticles (M-MSN) that are functionalized with ceria nanoparticles (CNPs) and anti-tau antibodies (AT8) as a potential therapeutic for AD127.In vitro studies showed the potential for CNPs to promote autophagy and prevent pathogenic tau accumulation. The functionalization of the NPs with AT8 facilitated the binding and accumulation of the NPs to pathological tau phosphorylation sites, such as Ser202/Thr205127,128. In vivo studies by Sun et al. indicated that the formulated NPs improved neuronal viability and cognitive functions and decreased pathogenic tau burden. These benefits are likely because the formulated NPs reduce microglial activation. Other in vitro and in vivo studies confirmed that the AT8-CNP-M-MSN NPs degraded pathogenic tau by inhibiting the AKT/mTOR signaling pathway. These NPs have also demonstrated high binding affinity for hyperphosphorylated tau, while minimizing interference with other biological proteins.