The progressive debilitating nature of rheumatoid arthritis (RA) combined with its unknown etiology and initial similarity to other inflammatory diseases makes early diagnosis a significant challenge. Early recognition and treatment of RA is essential for achieving effective therapeutic outcome. NIR‐II photoacoustic (PA) molecular imaging (PMI) is emerging as a promising new strategy for effective diagnosis and treatment guidance of RA, owing to its high sensitivity and specificity at large penetration depth. Herein, an antirheumatic targeted drug tocilizumab (TCZ) is conjugated to polymer nanoparticles (PNPs) to develop the first NIR‐II theranostic nanoplatform, named TCZ‐PNPs, for PA‐imaging‐guided therapy of RA. The TCZ‐PNPs are demonstrated to have strong NIR‐II extinction coefficient, high photostability and excellent biocompatibility. NIR‐II PMI results reveal the excellent targeting abilities of TCZ‐PNPs for the effective noninvasive diagnosis of RA joint tissue with a high signal‐to noise ratio (SNR) of 35.8 dB in 3D PA tomography images. Remarkably, one‐month treatment and PA monitoring using TCZ‐PNPs shows RA is significantly suppressed. In addition, the therapeutic evaluation of RA mice by NIR‐II PMI is shown to be consistent with clinical micro‐CT and histological analysis. The TCZ‐PNPs‐assisted NIR‐II PMI provides a new strategy for RA theranostics, therapeutic monitoring and the beyond.

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.

The conventional photoacoustic microscopy (PAM) system allows trade-offs between lateral resolution and imaging depth, limiting its applications in biological imaging in vivo. Here we present an integrated optical-resolution (OR) and acoustic-resolution (AR) multiscale PAM based on free-space light transmission and fast microelectromechanical systems (MEMS) scanning. The lateral resolution for OR is 4.9 µm, and the lateral resolution for AR is 114.5 µm. The maximum imaging depth for OR is 0.7 mm, and the maximum imaging depth for AR is 4.1 mm. The imaging speed can reach 50 k Alines per second. The high signal-to-noise ratios and wavelength throughput are achieved by delivering light via free-space, and the high speed is achieved by a MEMS scanning mirror. The blood vasculature from superficial skin to the deep tissue of a mouse leg was imaged in vivo using two different resolutions to demonstrate the multiscale imaging capability.

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