A smart ultra-small near infrared persistent luminescence nanoprobe for non-invasive detection of early rheumatoid arthritis

Early detection of rheumatoid arthritis (E-RA) is crucial for long-term patient health, but current methods lack precision. Overproduced reactive oxygen species (ROS) in hypoxic and inflammatory synovium are early markers of RA, appearing years before significant radiological findings, making them attractive biomarkers for early detection. Here, an ultrasensitive ROS-responsive nanoprobe are developed based on glutathione (GSH) modified Cr^3 + doped ZnGa₂O₄ ultra-small near-infrared (NIR) persistent luminescence nanoparticles (denoted as ZnGa₂O₄:Cr³⁺-GSH). The well-designed ZnGa₂O₄:Cr³⁺-GSH responds to ROS and cross-link by forming disulfide bonds, enabling autofluorescence-free NIR persistent luminescence (NIR-PL) imaging in vivo with a 1.9-fold signal to noise ratio (SNR) increase in collagen-induced arthritis mice paws compared to healthy control. Leveraging its ROS-responsive crosslinking and superior SNR performance, ZnGa₂O₄:Cr³⁺-GSH achieves ultrasensitive E-RA lesion detection through NIR-PL imaging. In addition, pharmacokinetic analysis shows that ultra-small ZnGa₂O₄:Cr³⁺-GSH has an elimination half-life of 19.85 min, with 3.45 % ID and 20.43 % ID excreted via urine and feces at 2 days post-injection, confirming its excellent biosafety. The study demonstrates the clinical promise of ZnGa₂O₄:Cr³⁺-GSH for precise diagnosis of E-RA, which might also offer an alternative basis for existing diagnostic procedures of RA.