An Intelligent AIEgen-Functionalized Hyaluronic Acid Nanocarrier for NIR-II Imaging-Guided and Stimuli-Regulated Rheumatoid Arthritis Theranostics

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Rheumatoid arthritis (RA) remains difficult to manage because of insufficient lesion visualization, limited targeted intervention against multiple pathological processes, and uncontrolled therapeutic activation. Conventional theranostic nanomedicines often require co-loading of multiple functional components, increasing formulation complexity while underutilizing the carrier itself. Herein, we report an intelligent AIEgen-functionalized hyaluronic acid nanocarrier, NDI@HA, as a carrier-intrinsic theranostic platform for RA. NDI@HA is constructed by conjugating an AIE-active NIR-II emissive photothermal molecule, NDI-NH2, onto hyaluronic acid through dynamic Schiff base bonds, endowing the carrier with intrinsic inflammation targeting, NIR-II fluorescence, photothermal activity, and pH/thermal responsiveness. Resveratrol (RES) is further loaded to obtain RES-NDI@HA nanoparticles. After HA-CD44-mediated accumulation in inflamed joints, acidic pH and NIR laser-induced hyperthermia trigger Schiff base cleavage, carrier disassembly, NDI-NH2 aggregation-to-dispersion transition, photothermal restoration, and on-demand RES release. NIR-II fluorescence and photothermal imaging enable real-time visualization of joint accumulation and imaging-guided intervention. In a rat RA model, RES-NDI@HA synergistically ablates aberrant fibroblast-like synoviocytes, promotes macrophage repolarization from M1 to M2, scavenges reactive oxygen species, and alleviates inflammation and joint destruction. This work provides a carrier-centered strategy for precise RA theranostics.

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