Implant failure, which is commonly associated with failure of osseointegration and peri-implant infection, is a severe complication of orthopedic surgery. In particular, the survival rate of implants is significantly decreased in patients using long-term glucocorticoids (GCs). However, the exact molecular mechanism underlying GCs-induced implant loosening, as well as preventive strategies for these patients, is unclear. To address this problem, we performed RNA-sequencing and found that WNT16 was correlated with GCs-induced osteopenia (LogFC = -5.17, p ＜ 0.01). Inspired by the concept of "organic-inorganic" hybrid, we theorized to introduce a bioactive two-dimensional nanosheet into a layer-by-layer (LbL) self-assembly coating to construct a customized implant that targets WNT16. After screening commercially available nanosheets, laponite (LAP) was identified as a cost-effective rescuer for GCs-induced WNT16 inhibition, which was then intercalated into LbL deposition system consisting of quaternized chitosan (QCS) and hyaluronic acid (HA). The hybrid coating (QCS/HA/LAP) showed micrometer thickness and improved hydrophilicity and interface roughness. Furthermore, QCS/HA/LAP coated polyetheretherketone (PEEK) implant enhanced cell viability, adhesion, and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), and promoted osteointegration of PEEK in GCs-treated rats by targeting the WNT16/β-catenin axis. The assembled QCS has proven antibacterial properties, and the hybrid coating exerted potent detrimental effects against methicillin-resistant (MRSA) and (), both and . Taken together, these results suggest that QCS/HA/LAP coating has great potential for use in implants customization, and has synergistic pro-osteogenic and antibacterial effects that help prevent implant failure in GCs-treated patients.