Background <p>This study aimed to investigate whether human periodontal ligament stem cells (hPDLSCs)-derived small extracellular vesicles (P-sEVs) can improve the periodontal inflammatory microenvironment and promote periodontal tissue regeneration by regulating macrophage pyroptosis.</p> Methods <p>The expression of the GSDMD and CD68 were examined using HE and IHC in healthy and periodontitis gingival tissues. Pyroptotic levels in macrophages co-cultured with hPDLSCs or P-sEVs were assessed using various methods in vitro. The hydroxybutyl chitosan hydrogel (HBCH)/P-sEVs repair system was implanted into a rat periodontitis bone defect model in vivo.</p> Results <p>GSDMD and CD68 were significantly elevated in inflamed gingival tissues. Treatment with <i>P. gingivalis</i>-LPS and ATP significantly upregulated the expression of NF-κB, NLRP3, caspase-1, GSDMD-N, IL-1β, and so on at both mRNA and protein levels, and significantly enhancing lactate dehydrogenase release, the percentage of cells with damaged membranes and so on. However, these pathological effects were mitigated by the paracrine effects of hPDLSCs or direct action of P-sEVs. The HBCH/P-sEVs repair system enhanced hPDLSCs proliferation and osteogenesis, while simultaneously reducing pyroptosis and promoting alveolar bone regeneration in rats.</p> Conclusions <p>P-sEVs significantly reduced macrophages pyroptosis induced by <i>P. gingivalis</i>-LPS/ATP by inhibiting the NF-κB/NLRP3/GSDMD signalling pathway in vitro. Furthermore, P-sEVs could be integrated with temperature-sensitive HBCH to establish a repair and regeneration system with potential clinical applications in the treatment of periodontitis.</p>