Self-cascade oxygen-generating hydrogel/nanofibrous membrane composites restore periodontal microenvironment homeostasis

The hypoxic environment of deep periodontal pockets favors the thriving of anaerobic microbes, leading to dysbiosis, tissue destruction, and treatment resistance. Elevating intra-pocket oxygen tension is a fundamental yet unmet need for controlling anaerobic pathogens in deep periodontal pockets. Our previous study demonstrated the therapeutic efficacy of oxygen-releasing hydrogel based on calcium peroxide (CPO) in reducing anaerobic pathogens in vitro. However, the rapid hydrolysis of unprotected CPO in an aqueous system and the potential oxidative damage induced by the intermediate hydrogen peroxide (H 2 O 2 ) limit its clinical applicability. To address these issues, we developed a dual-layer, self-cascade oxygen-generating composite (PCA-GC) to sustain topical oxygen enrichment in deep periodontal pockets. The inner layer consists of a hydrophobic polycaprolactone (PCL) nanofibrous membrane encapsulating CPO (designated PCA) to achieve long-term stability and controlled hydrolysis. Surrounding this core, a flexible gelatin methacryloyl-cerium oxide hydrogel (GC) served as a protective outer layer to decompose self-generated H 2 O 2 via its catalase-like activity, thereby preventing H 2 O 2 accumulation and shielding adjacent tissues. Our results showed that PCA-GC sustained oxygen release for up to 5 days, demonstrating satisfactory biocompatibility with human gingival fibroblasts and periodontal ligament cells. Furthermore, PCA-GC significantly alleviated hypoxia in multispecies biofilms and effectively eradicated periodontal pathogens, including Porphyromonas gingivalis (P. gingivalis) and Fusobacterium nucleatum (F. nucleatum) . In multispecies biofilms, the proportion of P. gingivalis decreased significantly from 84.42% to 0.05%, while the commensal Streptococcus gordonii increased from 11.18% to 99.01%, reflecting a shift from a pathogen-dominated to a commensal-dominated microbial community. Additionally, PCA-GC enhanced pathogen-clearance function in macrophages under hypoxia by increasing reactive oxygen species and nitric oxide production. In rat experimental periodontitis models, PCA-GC decreased hypoxia marker expression, reduced pathogen burden and alveolar bone loss, suppressed osteoclast activity, and attenuated inflammatory response. Collectively, sustained oxygen therapy via PCA-GC effectively remodels the periodontal microenvironment, suppresses pathogenic dysbiosis, and enhances host antimicrobial responses, underscoring its potential as an adjunctive strategy for treating periodontitis.