The interaction between biomaterials and immune system is a critical area of research, especially in tissue engineering and regenerative medicine. A fascinating and less explored aspect involves the immunomodulatory behaviors of macrophage (MΦ)-derived exosomes induced by biomaterial surfaces. Herein, untreated surface, nanostructured surface, and type I collagen (Col-I)-decorated nanostructured surface of titanium implants are chosen to culture MΦs, followed by extraction of MΦ-derived exosomes and investigation of their immunomodulatory functions and mechanisms. The results show that the exosomes in the untreated group carried plenty of inflammatory cytokines, predominantly C─C motif chemokine ligand 2 (CCL2). After targeting recipient cells, the CCL2 on the exosomes can specifically bind to its receptor C─C motif chemokine receptor 2, triggering downstream signaling pathways to induce internalization of membrane integrin β1 and targeted lysosomal degradation, consequently suppressing the functions of recipient cells. In contrast, the exosomes in the nanostructured group, especially Col-I-decorated nanostructured group carried few CCL2, moderating their inhibition on the functions of recipient cells. These findings not only clearly show that CCL2 is a key constituent of exosomes involved in the interaction between biomaterials and host immune system, but also potentially a key target for designing advanced biomaterials to promote tissue repair and regeneration.