Background <p>​Periodontal bone defects present significant challenges in clinical regeneration. Titanium mesh has been widely used in guided bone regeneration (GBR) due to its excellent mechanical properties, but its bioinert nature and potential immune response limit its regenerative efficacy. Surface modification of titanium alloys represents a promising approach to enhance their bioactivity. This study explores a novel strategy using polydopamine (PDA)-mediated lithium (Li) ion (Li⁺)loading on titanium surfaces to simultaneously promote osteogenesis and immunomodulation.</p> Methods <p>​Titanium discs were modified through alkali-thermal treatment, PDA coating, and lithium chloride(LiCl) immersion at different concentrations (1, 5, and 10&#xa0;mol/L). Surface characterization was performed using scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS). Li⁺ release kinetics and surface hydrophilicity were systematically evaluated. In vitro biological effects were assessed using rat bone marrow stromal cells (rBMSCs) and RAW264.7 macrophages through comprehensive analyses of cell adhesion, proliferation, osteogenic differentiation (Alkaline phosphatase (ALP) activity, mineralization, and gene expression), and macrophage polarization (inflammatory cytokine profiling). Conditioned medium(CM) collected from the co‑culture of macrophages and Ti‑PDA‑5Li was further used to evaluate the effects of the immune microenvironment on the proliferation and osteogenic activity of bone marrow stromal cells (BMSCs).</p> Results <p>​The modified surfaces exhibited a well-defined porous nanostructure, with Li⁺ incorporation significantly enhancing surface bioactivity. The Ti-PDA-5Li group demonstrated optimal performance with sustained Li⁺ release and improved hydrophilicity. This group significantly promoted rBMSC adhesion, proliferation, and osteogenic differentiation, showing enhanced ALP activity, mineralized nodule formation, and upregulation of osteogenic markers (<i>Runx2</i>,<i> OCN</i>,<i> BSP</i>,<i> OPN</i>). Moreover, Ti-PDA-5Li effectively modulated macrophage polarization towards the anti-inflammatory M2 phenotype, characterized by suppressed the level of pro-inflammatory cytokines (IL-6, TNF-α) and enhanced the level of anti-inflammatory factors (IL-10). CM from macrophages cultured on Ti-PDA-5Li further stimulated osteogenic differentiation in rBMSCs, confirming the immunomodulatory-osteogenic coupling effect.</p> Conclusions <p>​The PDA-assisted Li⁺ loading strategy successfully creates a bioactive titanium coating that synergistically promotes bone regeneration through direct osteogenic stimulation and immune microenvironment regulation. This study provides new insights into the development of multifunctional titanium implants for bone regeneration, highlighting the importance of combined osteo-immunomodulatory approaches.</p>