LAUSR

2D covalent organic frameworks (COFs) are an emerging class of crystalline porous organic polymers with a wide‐range of potential applications. However, poor processability, aqueous instability, and low water dispersibility greatly limit their practical biomedical implementation. Herein, a new class of hydrolytically stable 2D COFs for sustained delivery of drugs to direct stem cell fate is reported. Specifically, a boronate‐based COF (COF‐5) is stabilized using amphiphilic polymer Pluronic F127 (PLU) to produce COF‐PLU nanoparticles with thickness of ≈25 nm and diameter ≈200 nm. These nanoparticles are internalized via clathrin‐mediated endocytosis and have high cytocompatibility (half‐inhibitory concentration ≈1 mg mL−1). Interestingly, the 2D COFs induce osteogenic differentiation in human mesenchymal stem cells, which is unique. In addition, an osteogenic agent—dexamethasone—is able to be loaded within the porous structure of COFs for sustained delivery which further enhances the osteoinductive ability. These results demonstrate for the first time the fabrication of hydrolytically stable 2D COFs for sustained delivery of dexamethasone and demonstrate its osteoinductive characteristics.