Radicals Scavenging MOFs Enabling Targeting Delivery of siRNA for Rheumatoid Arthritis Therapy

Abstract

cell immersion. The progress of RA causes obvious joint pain to patient, resulting in joint destruction, bone and cartilage damage, and ultimate joint disability. RA is still incurable, and current treatment drugs can only alleviate symptoms, such as disease-modifying anti-rheumatic drugs, non-steroidal anti-inflammatory drugs, glucocorticoids (GCs), and biological agents. [2] However, most of these drugs require long-term administration, which not only brings financial burden to patients but also causes a series of adverse effects. Therefore, it is urgently desired to develop etiological treatments to cure RA based on the pathogenesis of the disease. Substantial evidences have revealed that autoantigens are important initiation factor of RA development, and macrophages play an important role in the progression of the disease. [3,4] The autoantigens include citrullinated peptides/ proteins and biomacromolecules modified by the overproduced reactive oxygen and nitrogen species (RONS), [5][6][7] which stimulate body's immune cells to secrete antibodies. Immune complexes of antibodies-autoantigens binding are then formed and tend to deposit in joint site to induce inflammation and recruit macrophages. [3] The recruited macrophages in RA microenvironment are mainly polarized to pro-inflammatory M1 phenotype with abundant cytokines secretion and RONS generation via respiratory burst, giving a positive feedback loop to exacerbate inflammation. [8,9] Thus, macrophages have been recognized as an important therapeutic target, and synergistic elimination of cytokines and RONS is a promising strategy for RA therapy.Nanomedicine has emerged as a robust strategy for targeted RA therapy. By virtue of the leaky vasculature formed during the progression of RA, nanoparticles with specific size range can be passively accumulated into inflamed synovial tissues through the defined extravasation through leaky vasculature and subsequent inflammatory cell-mediated sequestration (ELVIS) effect. [10,11] Moreover, the M1 polarized macrophages overexpress various receptors on cell membrane (e.g., folate receptor, scavenger receptor, CD44), which provides an opportunity for the design of active targeting systems via ligands modification on nanoparticle surface. For example, we recently reported hyaluronic acid (HA) and folic acid (FA) decorated nanoparticles to deliver methotrexate and RONS scavenging nanomaterials into the diseased macrophages at RA site. [12,13] Macrophages play essential roles in the progression of rheumatoid arthritis (RA), which are polarized into the pro-inflammatory M1 phenotype with significant oxidative stress and cytokines excretion. Herein, an active targeting nanomedicine based on metal-organic frameworks (MOFs) to re-educate the diseased macrophages for RA therapy is reported. The MOFs are prepared via coordination between tannic acid (TA) and Fe 3+ , and anti-TNF-α siRNA is loaded via a simple sonication process, achieving high loading capacity comparable to cationic vectors. The MOFs show excellent biocompati...

Combining nanotechnology with monoclonal antibody drugs for rheumatoid arthritis treatments

“…Furthermore, after nanosystems finish the delivery task, the residual nanocarriers can also have a positive effect on the treatment of RA rather than waste. To this end, Zhou et al [ 9 , 10 ] prepared tannic acid-based MOF and folic acid-anchored silver nanoparticles. Both of these two nanosystems primarily deliver anti-rheumatic drugs to the joints.…”

“…Macrophages, which are involved in the body’s nonspecific immunity, produce related inflammatory factors such as IL-1, IL-6, and TNF-α. These cytokines will stimulate FLSs and further activate osteoclasts (OCs), leading to bone damage [ 9 – 11 ]. Reports have shown that receptor activator for nuclear factor-κ B ligand (RANKL) is indispensable in osteoclast differentiation and activation, and the number and activity of osteoclasts are key factors in bone destruction [ 13 , 14 ].…”

A pH-responsive metal-organic framework for the co-delivery of HIF-2α siRNA and curcumin for enhanced therapy of osteoarthritis

“…The obtained solutions were centrifuged, the precipitations of MCS NPs were resuspended in 10 μL DEPC-treated water, and the supernatants were collected for comparison. The samples were loaded onto the preheated 4% agarose gel by using a previous reported method [ 55 ]. Then, the electrophoresis experiment was performed at 180 V for 20 min, and the gel was stained with ethidium bromide solution for 30 min.…”

Recent advances of metal-based nanoparticles in nucleic acid delivery for therapeutic applications

“…Biocompatible iron (3) carboxylate MOFs as RNA nanocarriers increased cellular uptake and gene activity in vitro [ 188 ]. Bovine Serum Albumin (BSA)-decorated MOF/anti-TNF-α siRNA showed high therapeutic efficacy against rheumatoid arthritis in collagen-induced arthritis (CIA) mice model [ 189 ].…”