The high level of reactive oxygen species (ROS) in the rheumatoid arthritis (RA) microenvironment (RAM) and its persistent inflammatory nature can promote damage to joints, bones, and the synovium. Targeting strategies that integrate effective RAM regulation with imaging-based monitoring could lead to improvements in the diagnosis and treatment of RA. Here, we report the combined use of small interfering RNAs (siRNAs T/I ) and Prussian blue nanoparticles (PBNPs) to silence the expression of proinflammatory cytokines TNF-α/IL-6 and scavenge the ROS associated with RAM. To enhance the in vitro and in vivo biological stability, biocompatibility, and targeting capability of the siRNAs T/I and PBNPs, macrophage membrane vesicles were used to prepare biomimetic nanoparticles, M@P-siRNAs T/I . The resulting constructs were found to suppress tumor necrosis factor-α/interleukin-6 expression and overcome the hypoxic nature of RAM, thus alleviating RA-induced joint damage in a mouse model. The M@P-siRNAs T/I of this study could be monitored via near-infrared photoacoustic (PA) imaging. Moreover, multispectral PA imaging without the need for labeling permitted the real-time evaluation of M@P-siRNAs T/I as a putative RA treatment. Clinical microcomputed tomography and histological analysis confirmed the effectiveness of the treatment. We thus suggest that macrophage-biomimetic M@P-siRNAs T/I and their analogs assisted by PA imaging could provide a new strategy for RA diagnosis, treatment, and monitoring.

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