The Bioactive Interface of Titanium Implant with Both Anti‐Oxidative Stress and Immunomodulatory Properties for Enhancing Osseointegration under Diabetic Condition

Abstract The poor implant‐osseointegration under diabetic condition remains a challenge to be addressed urgently. Studies have confirmed that the diabetic pathological microenvironment is accompanied by excessive oxidative stress, imbalanced immune homeostasis, and persistent chronic inflammation, which seriously impairs the osteogenic process. Herein, a multifunctional bioactive interface with both anti‐oxidative stress and immunomodulatory properties is constructed on titanium implants. Briefly, manganese dioxide nanosheets are coated onto mesoporous polydopamine nanoparticles loaded with carbon monoxide gas precursor, namely MnO 2 ‐CO@MPDA NPs, and then they are integrated on the titanium implant to obtain MCM‐Ti. In the simulated diabetic microenvironment, under the action of MnO 2 nanoenzymes, MCM‐Ti can effectively eliminate intracellular reactive oxygen species while alleviating hypoxic state. Interestingly, the microenvironment mediates the responsive release of CO gas, which effectively drives macrophages toward M2 polarization, thereby ameliorating inflammatory response. The potential mechanism is that CO gas up‐regulates the expression of heme oxygenase‐1, further activating the Notch/Hes1/Stat3 signaling pathway. Furthermore, the conditioned medium derived from macrophages on MCM‐Ti surface significantly enhances the osteogenic differentiation of BMSCs. In a type 2 diabetic rat model, MCM‐Ti implant effectively alleviates the accompanying inflammation and enhances the osseointegration through the synergistic effects of resisting oxidative stress and remodeling immune homeostasis.