AE-MXene-modified titanium alloy promotes osseointegration by regulating the AMPK-MTOR-autophagy pathway in macrophage

Abstract Effective osseointegration requires successful interaction between an implant and the local bone and immune environments. Surface modification presents a promising strategy to enhance the biocompatibility and integration of titanium implants. Although emerging research on transition metal carbides and nitrides (MXenes) demonstrates their potential to improve implant integration by modulating macrophage behavior and osteogenesis, existing studies have not explored synergistic modification strategies or the specific molecular mechanisms linking immunomodulation to bone healing. To address this, we developed a novel alkali-etched MXene (AE-MXene) coating by integrating alkali etching with MXene nanosheet loading, creating a platform that simultaneously optimizes micro/nanoscale surface topography and bioactive functionality—a synergistic approach previously unreported for MXene-based implants. Through comprehensive in vitro and in vivo analyses, we demonstrate that the AE-MXene surface possesses potent antibacterial, anti-inflammatory, and pro-osteogenic properties. Notably, we reveal for the first time that AE-MXene activates the AMP-activated protein kinase (AMPK)–mechanistic target of rapamycin (mTOR) pathway in macrophages, significantly upregulating autophagy to drive enhanced osteogenesis and angiogenesis. These findings delineate a unique autophagy-mediated mechanism through which AE-MXene promotes osseointegration, distinguishing it from prior MXene implant studies and highlighting its therapeutic potential for immunomodulatory and antimicrobial applications. Graphical abstract