Redox Homeostasis Strategy for Inflammatory Macrophage Reprogramming in Rheumatoid Arthritis Based on Ceria Oxide Nanozyme-Complexed Biopolymeric Micelles

Abstract

The synovial tissues under rheumatoid arthritis conditions are usually infiltrated by inflammatory cells, particularly M1 macrophages with aberrant redox homeostasis, which causes rapid deterioration of articular structure and function. Herein, we created an ROS-responsive micelle (HA@RH-CeO X ) through the in situ host–guest complexation between ceria oxide nanozymes and hyaluronic acid biopolymers, which precisely delivered nanozyme and clinically approved rheumatoid arthritis drug Rhein (RH) to proinflammatory M1 macrophage populations in inflamed synovial tissues. The abundant cellular ROS could cleave the thioketal linker to trigger the release of RH and Ce. Specifically, the Ce3+/Ce4+ redox pair could present SOD-like enzymatic activity to rapidly decompose ROS and alleviate the oxidative stress in M1 macrophages, while RH could inhibit the TLR4 signaling in M1 macrophages, both of which could act in a concerted manner to induce their repolarization into anti-inflammatory M2 phenotype to ameliorate local inflammation and promote cartilage repair. Notably, rats bearing rheumatoid arthritis showed a drastic increase in the M1-to-M2 macrophage ratio from 1:0.48 to 1:1.91 in the inflamed tissue and significantly reduced inflammatory cytokine levels including TNF-α and IL-6 following the intra-articular injection of HA@RH-CeO X , accompanied by efficient cartilage regeneration and restored articular function. Overall, this study revealed an approach to in situ modulate the redox homeostasis in inflammatory macrophages and reprogram their polarization states through micelle-complexed biomimetic enzymes, which offers alternative opportunities for the treatment of rheumatoid arthritis.

Drug-Embedded Nanovesicles Assembled from Peptide-Decorated Hyaluronic Acid for Rheumatoid Arthritis Synergistic Therapy

“…After HA–FP treatment, the activation state was slightly weakened, suggesting that HA–FP retains some of the anti-inflammatory properties inherent in HA. The LPS-activated macrophages treated with HA–FP/Cur showed a round shape, indicating that Cur played an essential role in inhibiting the activation of macrophages and had excellent anti-inflammatory ability; this is also consistent with the results of previous studies. , …”

“…The brown-red area of the HA−FP/ Cur-treated rats was further reduced, and the number of TNFα-labeled cells was still higher than that in the normal rats (Figure 8B), but the number of IL-1β-labeled cells was consistent with that in the control rats. These results suggest that in situ generation of HA−FP/Cur nanovesicles can provide excellent anti-inflammatory properties and enhanced safety of Cur, 15 significantly restore bone functional balance, and reduce the secretion of inflammatory cytokines by decreasing the number of inflammatory macrophages in arthritic joints. 58,59 The CD68 staining results showed the same trend, suggesting that the loaded Cur combined with modified HA could effectively inhibit inflammation and treat arthritis.…”

“…The secretion of inflammatory cytokines decreased after HA–FP treatment and decreased further after HA–FP/Cur treatment, indicating that both modified HA and Cur could inhibit macrophage activation levels of inflammatory cytokines, including TNF-α and IL-1β, which are significantly reduced. This might be beneficial for cartilage regeneration and recovery of joint function . Flow cytometry was also used to analyze the apoptosis of macrophages.…”

“…Healthy joints are filled with synovial fluid composed of hyaluronic acid (HA), lubricants, and phospholipids. , Among them, HA, the main component of synovial fluid, plays an essential role in maintaining normal physiological functions of joints, such as hydration, lubrication, and interactions between extracellular matrix proteins and proteoglycans. − Owing to its lubrication effect, HA has been widely applied to reduce the friction, protect the articular cartilage, and relieve pain. , HA is also a key component of the extracellular matrix of cartilages and can be naturally degraded by hyaluronidase in living organisms . HA is also a biopolymer with intrinsic biocompatibility and M1 macrophage-targeting capability . Therefore, it is feasible and acceptable to employ HA for RA treatment based on its excellent lubrication function .…”

Ultrasound-Augmented Multienzyme-like Nanozyme Hydrogel Spray for Promoting Diabetic Wound Healing

“…Nanozymes are a class of nanomaterials with enzyme-like characteristics that have shown great potential as surrogates for natural enzymes in various applications. − In recent years, nanozymes have been employed in DFU treatment due to their advantages of regulating redox homeostasis to avoid reactive oxygen species (ROS) dependent inflammation . Assorted DFU nanozyme therapies have been established, such as antioxidant nanozyme therapies, , pro-oxidant nanozyme therapies, , combined antioxidant and pro-oxidant nanozyme therapies, and etc.…”