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.

Many nonlinear effects have been discovered and developed in photoacoustic imaging. These nonlinear mechanisms have been explored for different utilizations, such as enhancing imaging contrast, measuring tissue temperature, achieving super-resolution imaging, enabling functional imaging, and extracting important physical parameters. This review aims to introduce different nonlinear mechanisms in photoacoustics, underline the fundamental principles, highlight their representative applications, and outline the occurrence conditions and applicable range of each nonlinear mechanism. Furthermore, this review thoroughly discusses the nonlinearity rule concerning how the mathematical structure of the nonlinear dependence is correlated to its practical applications. This summarization is useful for identifying and guiding the potential applications of nonlinearity based on their mathematical expressions, and is helpful for new nonlinear mechanism discovery or implementation in the future, which facilitates further breakthroughs in nonlinear photoacoustics.

As a noninvasive deep-tissue imaging technique, photoacoustic (PA) imaging has great application potential in biomedicine and molecular diagnosis. The zinc ion (Zn2+), which is a necessary metal ion in the human body, plays a very important role in the regulation of gene transcription and metalloenzyme function. The imbalance of Zn2+ homeostasis is also associated with a variety of neurological diseases. Therefore, it is critically important to accurately image the steady-state changes of Zn2+ in vivo. However, no PA imaging method is currently available for Zn2+. To this end, we designed and synthesized the first PA probe of Zn2+, namely, CR-1 for in situ ratiometric imaging of Zn2+ in deep tissue in vivo. The CR-1molecule, combined with Zn2+, weakened the conjugation system of the π-electron in the CR-1 molecule, which resulted in the blue shift of its absorption peak from 710 nm to 532 nm. The PA signal intensity decreased at 710 nm and increased at 532 nm, and the ratiometric PA signal at these two wavelengths (PA532/PA710) showed a good linear relationship with the concentration of Zn2+ in the range of 0–50 μM, with a detection limit as low as 170 nM. Furthermore, this probe exhibits extremely fast responsiveness, is highly selective, and has excellent biocompatibility. We have used the developed PA probe for the ratiometric PA imaging of Zn2+ in the thigh tissue of mice, and we still can accurately image Zn2+ after covering chicken breast tissue on the surface of mice thigh. In light of these outstanding features, the developed PA probe has high potential for imaging Zn2+ in deep tissues; thus, it will open up new avenues for the study of the complex biochemical processes involving Zn2+ in vivo.