Macrophage-derived hybrid exosome-mimic nanovesicles loaded with black phosphorus for multimodal rheumatoid arthritis therapy

Rheumatoid arthritis (RA) is chronic inflammation characterized by abundant inflammatory cell infiltration and a major cause of joint function disruption. Despite current therapeutic strategies such as non-steroidal drugs or anti-cytokine biologics having shown promise for RA management, their side effects and clinical response rate remain unsatisfactory, attributed largely to the complicated pathomechanisms and multiplicity of the inflammatory cytokines. In this work, novel hybrid exosome-mimic nanovesicles equipped with broad-spectrum anti-inflammatory activity were developed for RA treatment. The hybrid nanovesicles (HNV) were prepared by fusing an M1 macrophage membrane into exosome-mimic nanovesicles extruded from M2 macrophages. The HNV inherit the anti-inflammatory properties of the M2 macrophages and cytokine receptors derived from the M1 membrane. Accordingly, the HNV possess comprehensive anti-inflammation activity via binding proinflammatory factors and releasing anti-inflammatory mediators. Furthermore, black phosphorus nanosheets (BP) were introduced into the HNV (HNV@BP) to eliminate inflammatory cells upon near-infrared (NIR) irradiation, which intrinsically decreases the inflammatory reaction. In a mouse model of collagen-induced arthritis, the HNV loaded with BP targeted and accumulated at the inflammed knee joints, exhibiting multimodal rheumatoid arthritis therapy combined with NIR irradiation through comprehensive inflammation suppression.