<i>N</i> -Acetylcysteine-Capped TLQP21-Containing Au Nanocages Alleviate Depression in Mice

Major depressive disorder (MDD) is the most prevalent neuropsychiatric disorder globally. Promising therapies for MDD are urgently needed due to the limited effectiveness, delayed efficacy, and non-negligible side effects of current treatments. Oxidative stress and neuroinflammation have been recognized as key contributors to MDD. Here, we developed an antioxidant <i>N</i>-acetylcysteine (NAC)-capped Au nanocage (TNNC) that entrapped VGF-derived peptide TLQP21 with neuro-immunomodulatory effects. Once internalized by cells suffering from oxidative stress, NAC was consumed, and TLQP21 was released from TNNC. TNNC administration alleviated MDD-like behaviors of the chronic unpredictable mild stress (CUMS)-exposed mice and effectively relieved oxidative stress in the brains. Moreover, TLQP21 in TNNC inhibits the activation, excessive synaptic pruning, and inflammatory responses of microglia through targeting the complement C1q receptor (C1qR) and complement C3a receptor 1 (C3aR1). This work provides a bioinspired strategy to target multiple pathogenic factors in one nanoparticle for the intervention of MDD and other diseases.