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 MnO 2 ‐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 MnO 2 ‐Mn 2+ 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 Mn 2+ can exert Fenton‐like activity to generate •OH from H 2 O 2 , thus providing the effective chemodynamic therapy(CDT). Moreover, the up‐regulation of H 2 O 2 by GOx‐catalysis not only sensitizes the MnO 2 ‐Mn 2+ 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 MnO 2 ‐Mn 2+ system. Meanwhile, the integration of activated Mn 2+ ‐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.