Ultrasound-Excited Protoporphyrin IX-Modified Multifunctional Nanoparticles as a Strong Inhibitor of Tau Phosphorylation and β‑Amyloid Aggregation

Alzheimer’s disease (AD) has become one of the most serious societal problems globally, with no effective treatments. Parenchymal accumulation of amyloid beta (Aβ) plaques and the formation of neurofibrillary tangles are the hallmarks of AD. Their possible interactions and synergistic effects in AD have been gradually elucidated. The failure of many clinical trials suggests that it is difficult to treat AD with a focus on a single target. Instead, multiple targets may be an important direction for AD drug research. In this study, we used protoporphyrin IX (PX)-modified oxidized mesoporous carbon nanospheres (OMCN) (PX@OMCN@PEG­(OP)@RVGs) as a novel AD multifunctional nanodrug having multiple targets. The nanodrug efficiently inhibits tau phosphorylation. In addition, the use of PX with focused ultrasound triggered the production of reactive oxygen species that significantly inhibited Aβ aggregation. Both approaches notably increased the cognitive level of APP/PS1 transgenic (Tg) mice and ultimately achieved dual-target inhibition of AD. Furthermore, the safe and effective delivery of PX across the blood–brain barrier (BBB) due to modification of the RVG peptide was demonstrated in vivo and in vitro. The favorable photothermal effect of the nanoparticles improved the BBB permeability of PX@OP@RVGs under near-infrared irradiation. The results demonstrated that the novel PX@OP@RVG multifunctional nanomedicine has a dual-target treatment capability for AD and can traverse the BBB, indicating the potential for the effective treatment of AD.