Homology-Activated Ultrasensitive Nanomedicines for Precise NIR-II FL/MRI Imaging-Guided "Knock-On" Dynamic Therapy in Rheumatoid Arthritis

Abstract

Stimuli-responsive nanomedicines represent a pivotal technology for in situ on-demand drug release and offer multiple advantages over conventional drug delivery systems to combat rheumatoid arthritis(RA). However, the lack of sensitivity to a single-stimuli source or the inability to synchronize multi-stimuli responses can easily lead to challenges in achieving precise-theranostics of RA. Herein, a homology-activated ultrasensitive nanomedicines MnO₂-CQ4T-GOx(MCG NMs) is designed for NIR-II fluorescence(NIR-II FL)/magnetic resonance imaging(MRI)-guided effective "knock-on" dynamic anti-RA therapy. Building upon the characteristics of the RA-microenvironment, the MCG innovatively construct a MnO₂-Mn²⁺ system, which can normalized activation sites. The ultrasensitive-responsive degradation is achieved using the multi-stimuli processes in the RA-microenvironment, triggering release of functional small molecules. The produced Mn²⁺ can exert Fenton-like activity to generate •OH from H₂O₂, thus providing the effective chemodynamic therapy(CDT). Moreover, the up-regulation of H₂O₂ by GOx-catalysis not only sensitizes the MnO₂-Mn²⁺ system but also achieves self-enhancing CDT efficacy. The NIR-II FL quenching of CQ4T-BSA in the aggregated state occurs in MCG NMs, which can be rapidly and precisely "turn-on" via the MnO₂-Mn²⁺ system. Meanwhile, the integration of activated Mn²⁺-based MRI imaging has successfully developed an activatable dual-modal imaging. Feedback imaging-guided precise photodynamic therapy of CQ4T-BSA can achieve efficient "knock-on" dynamic therapy for RA.

Keywords: NIR‐II fluorescence imaging; dual‐modal Imaging; microenvironment; multi‐stimuli‐responsive nanomedicines; rheumatoid arthritis.