An imbalance between the innate and adaptive immunity after traumatic spinal cord injury (SCI) triggers excessive inflammatory activation, which ultimately leads to secondary neuronal damage and functional impairment. Importantly, inducing tolerance in both the innate and adaptive immunity helps suppress neuroinflammation and promotes neuroprotection. Innate immune tolerance triggered by lipopolysaccharides (LPS) is rapid, specific, and long-lasting; however, direct administration may cause significant side effects. Similarly, administering self-antigens after SCI can foster adaptive immune tolerance but may worsen tissue damage. Extracellular vesicles (EVs), as highly biocompatible natural carriers, address these challenges and deliver immunoregulatory signals to establish immune-tolerant microenvironments. Therefore, we preconditioned macrophages with a combination of low-dose LPS and self-antigens (myelin debris) to induce an immune-tolerant phenotype and isolated the resulting EVs trained with low-dose LPS and self-antigens (Trained-EVs). Our results demonstrate that Trained-EVs can effectively enhance innate immune tolerance and modulate adaptive immunity, thereby establishing a tolerogenic immune microenvironment. This dual strategy for inducing tolerance is a promising immunotherapeutic option for autoimmune and inflammatory diseases.