BACKGROUND: Depression is a prevalent mental disorder characterized by persistent low mood, loss of interest, and cognitive impairment. Oxidative stress and inflammation play crucial roles in its pathogenesis. Novel therapeutic strategies targeting these mechanisms are needed to improve treatment outcomes. PURPOSE: The purpose of this study is to gauge the therapeutic effectiveness of geniposide (GEN)-loaded umbilical cord-derived mesenchymal stem cell membrane biomimetic nanovesicles (CSPG@UMSC NPs) targeting the P2ry12 factor for depression management, considering its association with oxidative stress and inflammatory pathways. STUDY DESIGN: A combination of in vitro neuronal cell culture experiments and an in vivo chronic unpredictable mild stress (CUMS) mouse model was used to assess the effects of CSPG@UMSC NPs. METHODS: In vitro investigations involved culture and characterization of CSPG@UMSC NPs and transcriptome sequencing analysis to identify DEGs in neurons. In vivo experiments utilized a depression mouse model treated with CSPG@UMSC NPs, followed by behavioral tests, biomarker analysis, and histological assessments. RESULTS: CSPG@UMSC NPs successfully downregulated P2ry12 expression, leading to improved neuronal activity, decreased inflammation, reduced cell apoptosis, and lowered reactive oxygen species levels in both in vitro and in vivo settings. CONCLUSION: CSPG@UMSC NPs loaded with GEN inhibit oxidative stress and inflammation by downregulating P2ry12. This research unveils, for the initial instance, the vital role of P2ry12 in depression and proposes a novel nano-therapy strategy based on MSCs and GEN, offering new insights and potential clinical applications for the treatment of depression.