Arthritis is a chronic inflammatory disease marked by synovial hyperplasia, pain, and cartilage degradation, yet current therapies lack tissue specificity, causing off-target side effects. To optimize receptor-dependent homing, we mapped CCR1, CCR2, CCR3, and CXCR4 in adipose-derived MSCs using blocking antibodies. Inhibiting these receptors significantly reduced MSC targeting toward inflamed synoviocytes and macrophages, prioritizing the CXCR4–SDF-1 axis for engineering. We therefore generated CXCR4-overexpressing MSCs and derived ectosomes, creating a dual-action platform that actively homes to SDF-1–rich joints and sequesters local SDF-1 via high-avidity CXCR4 display, blunting chemokine signaling and leukocyte recruitment. To further suppress downstream inflammation, CXCR4-ectosomes were fused with LNPs encapsulating anti-inflammatory miRNA, silencing key mediators such as NF-κB circuits in synovial and immune cells. In human RA-FLS and a CIA mouse model, CXCR4 overexpression enhanced targeted joint accumulation, while SDF-1 scavenging reduced chemokine signaling. Furthermore, ectosome–LNP miRNA delivery attenuated pro-inflammatory genes, mitigating joint inflammation and damage. Collectively, these data support a strategy coupling CXCR4-driven homing and SDF-1 scavenging with LNP–miRNA silencing for targeted arthritis therapy.