Effective control of inflammatory cytokines is crucial for controlling ankylosing spondylitis (AS). However, due to the complexity of cytokine networks, current therapies targeting individual cytokines often fall short of achieving satisfactory outcomes. Here, we developed mesenchymal stem cell (MSC)-like nanodecoys (denoted “MSC-NDs”) and evaluated their potential as a versatile anti-inflammatory therapeutic for AS. To improve membrane yield, microvesicles derived from MSCs via cytochalasin B (CB) stimulation were employed as substitutes for traditional membrane extractions. Proteomic analysis confirmed that CB-induced microvesicles retained a membrane protein profile comparable to that of conventionally isolated MSC membranes, while offering over twice the production efficiency. The resulting MSC-NDs effectively neutralized multiple proinflammatory cytokines and suppressed cytokine-induced osteogenic differentiation of MSCs in vitro. In a mouse model of AS, MSC-NDs significantly reduced systemic cytokine levels and effectively delayed pathological new bone formation. RNA sequencing of lumbar spine tissue further revealed widespread downregulation of genes involved in bone metabolism and inflammation. These findings underscore the therapeutic potential of MSC-like nanodecoys as a versatile anti-inflammatory platform for the treatment of AS and potentially other inflammatory disorders.