A Biocompatible Second Near-Infrared Nanozyme for Spatiotemporal and Non-Invasive Attenuation of Amyloid Deposition through Scalp and Skull

Phototherapy, such as photodynamic therapy and photothermal therapy, holds great potential for modulation of Alzheimer's β-amyloid (Aβ) self-assembly. Unfortunately, current works for phototherapy of Alzheimer's disease (AD) are just employing either visible or first near-infrared (NIR-I) light with limited tissue penetration, which can not avoid damaging nearby normal tissues of AD patients through the dense skull and scalp. To overcome the shortcomings of AD phototherapy, herein we report an amyloid targeting, N-doped three-dimensional mesoporous carbon nanosphere (KD8@N-MCNs) as a second near-infrared (NIR-II) PTT agent. This makes it possible for photothermal dissociation of Aβ aggregates through the scalp and skull in a NIR-II window without hurting nearby normal tissues. Besides, KD8@N-MCNs have both superoxide dismutase and catalase activities, which can scavenge intracellular superfluous reactive oxygen species and alleviate neuroinflammation in vivo. Furthermore, KD8@N-MCNs efficiently cross the blood–brain barrier owing to the covalently grafted target peptides of KLVFFAED on the nanosphere surface. In vivo studies demonstrate that KD8@N-MCNs decrease Aβ deposits, ameliorate memory deficits, and alleviate neuroinflammation in the 3xTg-AD mouse model. Our work provides a biocompatible and non-invasive way to attenuate AD-associated pathology.