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.