An upconversion nanoplatform based multi-effective theatment for Parkinson’s disease

•Oxidative stress and neuroinflammation are the key mechanisms in the occurrence and development of PD.•Precise controlled release of drug in the brain based on UCNP under near-infrared irradiation for the treatment of PD.•Controlled drug delivery to target the PD microenvironment through lactoferrin.•Combining NO nanocarriers (short-term) and traditional Chinese medicine Pae (long-term) achieved synergistic treatment of PD. Parkinson’s disease (PD) is a complex neurodegenerative disease affected by many factors. Although there are treatments to combat the symptoms of PD, such as levodopa and deep electrical stimulation, there is currently no ideal therapy to delay or prevent the progression of PD. Oxidative stress and neuroinflammation have been considered as the key mechanisms in the occurrence and development of PD. In theory, anti-oxidative stress and anti-neuroinflammation are effective strategies for the treatment of PD. In this work, we have attempted for the first time to construct a nitric oxide (NO) gas and drug combination therapeutic nanoplatform (Lf-UZSP) that can penetrate the blood–brain barrier (BBB) and target PD microenvironment through upconversion nanoparticles (UCNPs). The nanoplatform can target the PD microenvironment in the brain and subsequently convert near-infrared (NIR) light into ultraviolet (UV) light, which in turn releases NO, and the disintegration of NO gas further promotes the release of paeoniflorin (Pae). The controllable release of NO and Pae is used to achieve short-acting and long-acting synergistic therapy. In vitro experiments demonstrate that Lf-UZSP exhibits promising neuroprotective effects in PD cell models by scavenging excessive reactive oxygen species (ROS) and inhibiting neuroinflammation. Further in vivo experiments confirm that Lf-UZSP can significantly improve the motor impairment and alleviate the loss of dopaminergic (DA) neurons in the substantia nigra and striatum in PD mice.