<p>Extracellular vesicles released from mesenchymal stem cells (MSCs-EV) have shown anti-inflammatory effects in Parkinson’s disease (PD). This study was designed to assess the neuroprotective effects of human umbilical cord MSCs (hucMSCs) and the possible mechanisms involved. SH-SY5Y cells were induced with MPP⁺, and the impact of hucMSCs-EV on the damage to SH-SY5Y cells was examined. Mice were induced with PD-like symptoms by MPTP and the effects of hucMSCs-EV on neurological damage in mouse brain tissue were detected as well. HucMSCs-EV inhibited apoptosis and oxidative stress in MPP⁺-induced SH-SY5Y cells. HucMSCs-EV suppressed behavioral deficits and neuronal apoptosis in MPTP-induced mice, with an increased number of dopamine neurons in brain tissues and decreased p-alpha-syn expression in dopamine neurons. The expression of ribosomal protein S27A (RPS27A) in SH-SY5Y cells was elevated after co-culture of neurons and hucMSCs-EV, and RPS27A silencing abated the effect of hucMSCs-EV in vivo and in vitro. RPS27A bound to the MDM2 promoter, thus promoting P53 ubiquitination and degradation. MDM2 overexpression strengthened the therapeutic effect of hucMSCs-EV. We conclude that hucMSCs-EV promote the interaction between RPS27A and MDM2 by delivering RPS27A, which regulates the MDM2-P53 axis to promote degradation of P53 to ameliorate neurological damage in PD.</p>