Mesenchymal stem cells (MSCs) are potential therapeutics for the treatment of periodontal defects. It is increasingly accepted that MSCs mediate tissue repair through secretion of trophic factors, particularly exosomes. Here, we investigated the therapeutic effects of human MSC exosome-loaded collagen sponge for regeneration of surgically created periodontal intrabony defects in an immunocompetent rat model. We observed that relative to control rats, exosome-treated rats repaired the defects more efficiently with regeneration of periodontal tissues including newly-formed bone and periodontal ligament (PDL). We also observed that concomitant with this, there was increased cellular infiltration and proliferation. We therefore postulated that MSC exosomes enhanced regeneration through increased cellular mobilisation and proliferation. Using PDL cell cultures, we demonstrated that MSC exosomes could increase PDL cell migration and proliferation through CD73-mediated adenosine receptor activation of pro-survival AKT and ERK signalling. Inhibition of AKT or ERK phosphorylation suppressed PDL cell migration and proliferation. Our findings demonstrated for the first time that MSC exosomes enhance periodontal regeneration possibly by increasing PDL migration and proliferation. This study suggests that MSC exosome is a viable ready-to-use and cell-free MSC therapeutic for the treatment of periodontal defects. STATEMENT OF SIGNIFICANCE: Mesenchymal stem cell (MSC) therapies have demonstrated regenerative potential for the treatment of periodontal defects. However, translation of cellular therapies is hampered by challenges in maintaining optimal cell vitality and viability from manufacturing and storage to final delivery to patients. Although the use of MSCs for tissue repair was first predicated on their differentiation potential, the therapeutic efficacy of MSCs has increasingly been attributed to its paracrine secretion, particularly exosomes or small extracellular vesicles. In this study, MSC exosome-loaded collagen sponge enhanced periodontal regeneration in an immunocompetent rat periodontal defect model without any obvious adverse effects. These findings provide the basis for future development of MSC exosomes as a cell-free strategy for periodontal regeneration.