Alzheimer's disease (AD) remains the most prevalent
neurodegenerative disease, and no effective treatment is available yet.
Metal-ion-triggered aggregates of
amyloid-beta (Aβ)
peptide and
acetylcholine imbalance are reported to be possible factors in AD pathogenesis. Thus, a combination
therapy that can not only inhibit and reduce Aβ aggregation but also simultaneously regulate
acetylcholine imbalance that can serve as a potential treatment for AD is needed. Here,
clioquinol (
metal-ion
chelating agent) and
donepezil (
acetylcholinesterase (AChE) inhibitor) co-encapsulated
human serum albumin (HSA) nanoparticles (dcHGT NPs) are designed, which are modified with transcriptional activator
protein (TAT) and monosialotetrahexosylganglioside (GM1). The GM1
lipid and TAT
peptide endow this
drug delivery nanosystem with high brain entry efficiency and long-term retention capabilities through
intranasal administration. It is found that dcHGT NPs can significantly inhibit and eliminate Aβ aggregation, relieve
acetylcholine-related
inflammation in microglial cells, and protect primary neurons from Aβ oligomer-induced neurotoxicity in vitro. The alleviation of Aβ-related
inflammation and AChE-inhibited effect further synergistically adjust
acetylcholine imbalance. It is further demonstrated that dcHGT NPs reduce Aβ deposition, ameliorate neuron morphological changes, rescue
memory deficits, and greatly improve
acetylcholine regulation ability in vivo. This multifunctional synergetic nanosystem can be a new candidate to achieve highly efficient combination
therapy for AD.