A Smart Nanoreactor Based on an O 2 -Economized Dual Energy Inhibition Strategy Armed with Dual Multi-stimuli-Responsive "Doorkeepers" for Enhanced CDT/PTT of Rheumatoid Arthritis.

Activated fibroblast-like synovial (FLS) cells are regarded as an important target for rheumatoid arthritis (RA) treatment via starvation therapy mediated by glucose oxidase (GOx). However, the hypoxic RA-FLS environment greatly reduces the oxidation process of glucose and leads to a poor therapeutic effect of the GOx-based starvation therapy. In this work, we designed a hollow mesoporous copper sulfide nanoparticles (CuS NPs)-based smart GOx/atovaquone (ATO) codelivery system (named as V-HAGC) targeting RA-FLS cells to realize a O 2 -economized dual energy inhibition strategy to solve the limitation of GOx-based starvation therapy. V-HAGC armed with dual multi-stimuli-responsive "doorkeepers" can guard drugs intelligently. Once under the stimulation of photothermal and acidic conditions at the targeted area, the dual intelligent responsive "doors" would orderly open to realize the controllable release of drugs. Besides, the efficacy of V-HAGC would be much improved by the additional chemodynamic therapy (CDT) and photothermal therapy (PTT) stimulated by CuS NPs. Meanwhile, the upregulated H 2 O 2 and acid levels by starvation therapy would promote the Fenton-like reaction of CuS NPs under O 2 -economized dual energy inhibition, which could enhance the PTT and CDT efficacy as well. In vitro and in vivo evaluations revealed V-HAGC with much improved efficacy of this combination therapy for RA. In general, the smart V-HAGC based on the O 2 -economized dual energy inhibition strategy combined with enhanced CDT and PTT has the potential to be an alternative methodology in the treatment of RA.