A Smart Nanoreactor Based on an O₂-Economized Dual Energy Inhibition Strategy Armed with Dual Multi-stimuli-Responsive “Doorkeepers” for Enhanced CDT/PTT of Rheumatoid Arthritis

Abstract

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 O2-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 H2O2 and acid levels by starvation therapy would promote the Fenton-like reaction of CuS NPs under O2-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 O2-economized dual energy inhibition strategy combined with enhanced CDT and PTT has the potential to be an alternative methodology in the treatment of RA.

Defect-Rich Ni–CoO@PEG Porous Hexagonal Nanosheets: Multi-enzyme and Ultrasound Catalysis for Synergistic Anticancer Treatment

“…Glucose is a vital nutrient, whose metabolism would produce adenosine 5′-triphosphate (ATP) to power living cells. , The intracellular ATP level is tested by using the ATP assay kit to evaluate the starvation state. As displayed in Figure D, the intracellular ATP content decreases with the increase of sample concentration significantly.…”

Combining nanotechnology with monoclonal antibody drugs for rheumatoid arthritis treatments

“…Rheumatoid arthritis (RA) is an autoimmune disease that results in the infiltration of inflammatory cytokines and erosion of cartilage and bones, leading to joint swelling, pain, and bone damage, ultimately affecting the survival status and lifespan of patients [ 130 ]. Surgery cannot fundamentally solve the excessive immune status of patients, and it causes secondary injury to the patient as the joint synovium is removed.…”

Photothermal Nanomaterials: A Powerful Light-to-Heat Converter

“…Since silica-cored Au nanoshells served as the first photothermal nanomaterials for clinical use, more and more inorganic agents with strong absorption in the NIR region, high chemical stability, adjustable water solubility, and minimal cytotoxicity have entered clinical trials. , Clinical trials have also been underway for small organic molecules due to their good biodegradability, good repeatability, and simple preparation. , Nevertheless, the major challenges for the clinical implementation of photothermal nanomaterials are the complex metabolism and excretion behaviors . The representative works on PTT with diverse photothermal nanomaterials in recent years − are summarized in Table .…”