Abstract
Rheumatoid arthritis (RA) is one of the most common autoimmune diseases worldwide, causing severe cartilage damage and disability. Despite the recent progress made in RA treatment, limitations remain in achieving early and efficient therapeutic intervention. Advanced therapeutic strategies are in high demand, and siRNA-based therapeutic technology with a gene-silencing ability represents a new approach for RA treatment. In this study, we created a cationic delivery micelle consisting of low-molecular-weight (LMW) polyethylenimine (PEI)–cholesterol–polyethylene glycol (PEG) (LPCE) for small interfering RNA (siRNA)-based RA gene therapy. The carrier is based on LMW PEI and modified with cholesterol and PEG. With these two modifications, the LPCE micelle becomes multifunctional, and it efficiently delivered siRNA to macrophages with a high efficiency greater than 70%. The synthesized LPCE exhibits strong siRNA protection ability and high safety. By delivering nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 siRNA, the p65 siRNA/LPCE complex efficiently inhibited macrophage-based cytokine release in vitro. Local administration of the p65 siRNA/LPCE complex exhibited a fast and potent anti-inflammatory effect against RA in a mouse model. According to the results of this study, the functionalized LPCE micelle that we prepared has potential gene therapeutic implications for RA.
Highlights
Rheumatoid arthritis (RA) is one of the most common autoimmune diseases, with chronic arthritis as the main symptom, and it can cause cartilage and bone damage as well as disability [1]
We investigated the expression of NF-κB p65, TNF-α, IFN-γ, IL-1β, IL-6, and IL-10 in the synovium of mouse joints and found, in parallel with improved clinical indices and histology, that joint-associated inflammatory cytokine production was significantly regulated in mice treated with NF-κB p65 small interfering RNA (siRNA)/LMW PEI–cholesterol–PEG (LPCE) micelles
A new non-viral siRNA LPCE micelle vector was developed for siRNAIn this(Scheme research, newresults non-viral siRNA LPCE
Summary
Rheumatoid arthritis (RA) is one of the most common autoimmune diseases, with chronic arthritis as the main symptom, and it can cause cartilage and bone damage as well as disability [1]. As such, reversing its activity in macrophages during RA by siRNA-based gene silencing is believed to be a potential therapeutic strategy. The large amounts of enzymes contained in lysosomes challenges the gene/vector complex with a high degradation risk, and this further prevents siRNAs from functioning [21] For these reasons, siRNA-based RA gene therapy strategies are limited, despite the range of gene targets is widespread. We developed a novel LMW PEI–cholesterol–PEG (LPCE) delivery micelle for RA gene therapy based on NF-κB p65 siRNA. This carrier is based on LMW PEI and modified with cholesterol and PEG. We believe that our LPCE micelle could efficiently deliver p65 siRNA into macrophages in vivo, resulting in an early and fast anti-inflammation effect at the articular cavity with high safety. We examined the treatment effects and mechanisms of p65 siRNA/LPCE in a collagen-induced arthritis (CIA) model in vitro and in vivo
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