<p>Periodontitis, a globally prevalent inflammatory disease, is propelled by a vicious cycle involving microbial dysbiosis, hyperactive host immune responses, excessive oxidative stresses, and chronic inflammations. Current treatments largely focus on reducing microbial pathogens, yielding limited therapeutic efficacy. Here, we report a polydopamine-based taurolithocholic acid (TLCA) nanotherapeutic (PDCA) that reprograms versatile immuno-microbial cues to ameliorate periodontal inflammation and restore tissue homeostasis. Leveraging the dual function of polydopamine in drug delivery and redox capacity, after cellular uptake, PDCA scavenges reactive oxidation species, and releases TLCA to interact with its nuclear receptors in various target cells, exerting multifaceted regulatory effects. In inflamed human gingival fibroblasts, PDCA reduces the oxidative stress and enriches intracellular accumulation of TLCA to assist its interaction with vitamin D receptor, thus attenuating the expression of pro-inflammatory cytokines. Furthermore, PDCA modulates hyperactive immune responses, including suppressing the maturation of dendritic cells, inhibiting osteoclast differentiation of monocytes, downregulating pro-inflammatory CD4⁺ lymphocytes, and upregulating regulatory T cells. Concomitantly, this immunomodulation is associated with the restoration of periodontal microbiome homeostasis, contributing to a reduction in pathogens and an enrichment of beneficial flora. In addition, PDCA not only rescues inflammatory tissue destructions in both therapeutic and prophylactic mouse models of periodontitis, but also elicits robust decrement in pro-inflammatory cytokine production in ex vivo human periodontitis tissues. This work highlights polydopamine-based bile acid nanomedicine as a microenvironment-targeting platform for immuno-microbial rebalance, offering a transformative strategy to treat oral inflammatory diseases.</p> Graphical abstract <p></p>