Dual Targeting Biomimetic Carrier‐Free Nanosystems for Photo‐Chemotherapy of Rheumatoid Arthritis via Macrophage Apoptosis and Re‐Polarization

Abstract Rheumatoid arthritis (RA) is a common chronic systemic autoimmune disease that often results in irreversible joint erosion and disability. Methotrexate (MTX) is the first‐line drug against RA, but the significant side effects of long‐term administration limit its use. Therefore, new therapeutic strategies are needed for treating RA. Here, dual‐targeting biomimetic carrier‐free nanomaterials (BSA‐MTX‐CyI nanosystem, BMC) is developed for synergistic photo‐chemotherapy of RA. Bovine serum albumin (BSA), which has high affinity with SPARC (secreted protein acidic and rich in cysteine) in the RA joint microenvironment, is selected as the hydrophilic end and coupled with MTX and the phototherapeutic agent CyI to self‐assemble into BMC. In vitro and in vivo experiments revealed that BMC accumulated significantly at the joint site in collagen antibody‐induced arthritis mice and could be specifically recognized and taken up by folate receptors in proinflammatory M1 macrophages. Upon near‐infrared laser irradiation, CyI exerted photodynamic and photothermal effects, whereas MTX not only inhibited cell proliferation but also increased cell sensitivity to reactive oxygen species, enhancing the apoptotic effect induced by CyI and achieving synergistic photo‐chemotherapy. Moreover, BMC could induce macrophages to reprogram into anti‐inflammatory M2 macrophages. This study provides innovative approaches for RA treatment via macrophage apoptosis and re‐polarization.