Black phosphorus nanosheets as therapeutic “garbage trucks” for the selective clearance of peripheral phosphorylated Tau proteins in Alzheimer’s disease

The onset of Alzheimer's disease (AD) is closely related to the accumulation of phosphorylated Tau proteins (P-Tau). However, due to the hindrance posed by the blood–brain barrier (BBB), current therapies targeting brain-derived P-Tau are largely ineffective. Interestingly, the clearance of peripheral P-Tau can eliminate P-Tau from the brain, enabling AD treatment and overcoming the challenges created by the BBB. Here, we prepared polyethylene glycol (PEG)-modified black phosphorus nanosheets (BP-PEG), which showed extended systemic circulation and acted as efficient "garbage trucks" for the removal of peripheral P-Tau. BP-PEG exhibited an exceptional capacity to bind to P-Tau in vitro. Further, in vivo biodistribution analysis demonstrated that BP-PEG accumulated in the liver and kidneys, which are the same organs that metabolize P-Tau. In vivo studies revealed that in okadaic acid (OA)-induced mouse models of AD, BP-PEG significantly reduced the levels of P-Tau in both the peripheral blood and the brain. Moreover, by promoting the clearance of peripheral P-Tau, BP-PEG improved several health indicators in mice, including cognitive function, glucose metabolism in the brain, inflammatory markers in the plasma and hippocampus, oxidative stress, and mitochondrial and myelin morphology. In conclusion, this study provides a new strategy for AD treatment, demonstrating the therapeutic value of removing P-Tau from the peripheral blood, and it also represents a novel attempt for the application of BP-PEG in AD therapy.