Alan Alves Machado, Lara Steiner Back, Gilberto de Souza Melo, Reinhard Gruber, Ariadne Cristiane Cabral Cruz
Exosomes have emerged as promising cell-free therapeutic agents for tissue regeneration. However, chronic inflammation, a hallmark of periodontal disease, may impair their osteogenic potential. This systematic review evaluated how inflammatory conditions influence the ability of exosomes to modulate osteogenesis in human periodontal ligament stem cells (hPDLSC) in vitro. Electronic databases and grey literature were searched up to February 2026, and study selection followed a two-phase screening process. Risk of bias was assessed using the Risk of Bias in Dental Preclinical Research Tool (RobDMAT), while certainty of evidence was evaluated using adapted GRADE criteria. Primary outcomes included alkaline phosphatase (ALP) activity and extracellular matrix mineralization. Due to substantial heterogeneity across studies, a meta-analysis was not performed, and findings were synthesized qualitatively using fold-change comparisons. Six studies were included. Exosome-based interventions consistently enhanced osteogenic outcomes under inflammatory conditions, although with variable magnitude. Extracellular matrix mineralization showed robust increases (> 4-fold) in two studies (10.67- and 4.38-fold), moderate enhancement in one study (3.06-fold), and weak increases (< 2-fold) in three studies (1.95-, 1.60-, and 1.41-fold). ALP activity demonstrated predominantly moderate (3.04-, 3.30-, and 3.83-fold) to robust enhancement (5.50- and 6.75-fold). Limited evidence also suggested a reduction in pro-inflammatory mediators, although this outcome remains insufficiently explored. Exosomes appear to partially overcome the inhibitory effects of inflammation on osteogenesis in hPDLSC, supporting their potential as modulators of regenerative responses in inflammatory microenvironments. Nevertheless, the limited number of studies and methodological heterogeneity restrict the strength of current evidence.