"Swiss Army Knife" black phosphorus-based nanodelivery platform for synergistic antiparkinsonian therapy via remodeling the brain microenvironment.

The combination of excessive reactive oxygen species (ROS) levels, neuroinflammation, and pathogenic protein aggregation disrupt the homeostasis of brain microenvironment, creating conditions conducive to the progression of Parkinson's disease (PD). Restoring homeostasis by remodeling the brain microenvironment could reverse this complex pathological progression. However, treatment strategies that can induce this effect are currently unavailable. Herein, we developed a "Swiss Army Knife" nanodelivery platform consisting of matrine (MT) and polyethylene glycol-modified black phosphorus nanosheets (BP) that enables PD treatment by restoring brain microenvironment homeostasis. Under NIR irradiation, the photothermal effect induced by BP allowed the nanomedicine to cross the blood-brain barrier (BBB) and entered the brain parenchyma. In PD brains, the biological effects of BP and MT resulted in the removal of excess ROS, effective reduction of neuroinflammation, decreased aggregation of pathogenic proteins, and improved neurotransmitter delivery, eventually restoring dopamine levels in the striatum. This study demonstrated the effective capacity of a BP-based nanodelivery platform to enter the brain parenchyma and trigger multiple neuropathological changes in PD brains. The platform serves as a safe and effective anti-PD nanomedicine with immense clinical potential.