Engineered Probiotics with Low Oxygen Targeting <i>Porphyromonas gingivalis</i> and Gingival Fibroblasts for the Treatment of Periodontitis

The overuse of antibiotics has increased the prevalence of drug-resistant bacteria in periodontitis. "Sentinel" gingival fibroblasts, stimulated by pathogenic bacteria, continue to release signaling factors that affect stem cell repair and recruit immune cells, resulting in persistent inflammation in periodontal tissues, eventually leading to the loosening and loss of teeth. Periodontal pathogenic bacteria cause surface hypoxia, and gingival fibroblasts in the inflammatory microenvironment express HIF-1α, promoting hypoxic areas in periodontal pockets. No drug delivery system is available for the hypoxic region of periodontal pockets. We synthesized BI NPs via berberine (BBR) and indocyanine green (ICG) and formed BIP NPs by wrapping BI NPs with polydopamine (PDA), and the BIP NPs were delivered to the hypoxic region of the periodontal pocket by hitchhiking with the anaerobic probiotic <i>Bifidobacterium bifidum</i> (Bif). The BIP NPs released berberin (BBR) under near-infrared (NIR) irradiation, which inhibited the sulfur metabolism of <i>Porphyromonas gingivalis</i> via mild photothermal action and BBR-targeted serine acetyltransferase, resulting in a decrease in resistance to oxidative stress, thus exerting a nonantibiotic bacteriostatic effect. This mild photothermal effect facilitated the uptake of BIP NPs bygingival fibroblasts. Moreover, BBR targeted nuclear factor-erythroid 2-related factor 2 (NRF2) to reduce ferroptosis, and the gingival fibroblast supernatant modulated macrophage polarization through the NF-κB pathway. In the periodontitis rat model, Bif@BIP+NIR treatment carried the drug to deep periodontal pockets, decreasing local gingival ferroptosis and alleviating periodontitis symptoms. To summarize, engineered probiotics target low-oxygen periodontal pockets for drug delivery, <i>P. gingivalis</i> for nonantibiotic bacterial inhibition, and gingival fibroblasts to mitigate ferroptosis, thus alleviating periodontitis to reduce periodontitis.