Synthetic Nucleic Acid Antigens in Localized Scleroderma.

We investigated the impact of synthetic nucleic acid antigens on the autoantibody profiles in patients with localized scleroderma, an autoimmune skin disease. Anti-DNA antibodies, including double-stranded DNA (dsDNA) and single-stranded DNA (ssDNA), are common among autoimmune diseases, such as systemic lupus erythematosus and localized scleroderma. Based on recent studies, we hypothesized that the sequence of nucleic acid antigens has an impact on the autoimmune reactions in localized scleroderma. To test our hypothesis, we synthesized a panel of DNA and RNA antigens and used them for autoantibody profiling of 70 children with localized scleroderma compared with the healthy controls and patients with pediatric systemic lupus erythematosus (as a disease control). Among the tested antigens, dsD4, which contains the sequence of the human oncogene BRAF, showed a particularly strong presence in localized scleroderma but not systemic lupus erythematosus. Disease activity in patients was significantly associated with dsD4 autoantibody levels. We confirmed this result in vivo by using a bleomycin-induced mouse model of localized scleroderma. When administered intraperitoneally, dsD4 promoted an active polyclonal response in the mouse model. Our study highlights sequence specificity for nucleic acid antigens in localized scleroderma that could potentially lead to developing novel early-stage diagnostic tools.

Biomarkers in skin autoimmunity-An update on localised scleroderma.

Human autoimmune diseases are complex and highly diverse conditions that can be of localised or systemic nature. Understanding the basic biology of autoimmune diseases goes hand in hand with providing the clinics with valuable biomarkers for managing these diseases. The focus of this review is paid to localised scleroderma, an autoimmune disease affecting skin and subcutaneous tissue. Localised scleroderma has very few serological biomarkers for clinical analyses distinguishing it from main differentials, and yet noneffective prognostic biomarkers. With this regard, the review covers well-established and new biomarkers such as cell surface proteins, autoantibodies and cytokines. In recent few years, several new biomarkers have been suggested, many provided with modern genomic studies. This includes epigenetic regulation of DNA, RNA transcriptomics and regulatory RNA such as microRNA and long non-coding RNA. These findings can for the first time shed light on the genetic mechanisms behind the disease and contribute to improved diagnosis and treatment.

Pseudouridine and N1-methylpseudouridine as potent nucleotide analogues for RNA therapy and vaccine development.

Modified nucleosides are integral to modern drug development, serving as crucial building blocks for creating safer, more potent, and more precisely targeted therapeutic interventions. Nucleobase modifications often confer antiviral and anti-cancer activity as monomers. When incorporated into nucleic acid oligomers, they increase stability against degradation by enzymes, enhancing the drugs' lifespan within the body. Moreover, modification strategies can mitigate potential toxic effects and reduce immunogenicity, making drugs safer and better tolerated. Particularly, N1-methylpseudouridine modification improved the efficacy of the mRNA coding for spike protein of COVID-19. This became a crucial step for developing COVID-19 vaccine applied during the 2020 pandemic. This makes N1-methylpseudouridine, and its "parent" analogue pseudouridine, potent nucleotide analogues for future RNA therapy and vaccine development. This review focuses on the structure and properties of pseudouridine and N1-methylpseudouridine. RNA has a greater structural versatility, different conformation, and chemical reactivity than DNA. Watson-Crick pairing is not strictly followed by RNA that has more unusual base pairs and base-triplets. This requires detailed structural studies and structure-activity relationship analyses for RNA, also when modifications are incorporated. Recent successes in this direction are revised in this review. We describe recent successes with using pseudouridine and N1-methylpseudouridine in mRNA drug candidates. We also highlight remaining challenges that need to be solved to develop new mRNA vaccines and therapies.

Surface engineering of metal-organic framework nanoparticles-based miRNA carrier: Boosting RNA stability, intracellular delivery and synergistic therapy.

MicroRNAs (miRNAs) are small noncoding RNAs that are critical for the regulation of multiple physiological and pathological processes, thus holding great clinical potential. However, the therapeutic applications of miRNAs are severely limited by their biological instability and poor intracellular delivery. Herein, we describe a dual-layers surface engineering strategy to design an efficient miRNA delivery nanosystem based on metal-organic frameworks (MOFs) incorporating lipid coating. The resulting nanoparticle system was demonstrated to protect miRNA from ribonuclease degradation, enhance cellular uptake and facilitate lysosomal escape. These ensured effective miRNA mediated gene therapy, which synergized with MOF-specific photodynamic therapy and pre-encapsulated doxorubicin (Dox) chemotherapy to provide a multifunctional with therapeutic effectiveness against cencer cells The mechanisms of miRNA binding and Dox loading were revealed, demonstrating the potential of the present MOFs surface-engineered strategy to overcome their inherent pore-size restriction for macromolecular miRNA carrying, enableefficient co-delivery. In vitro studies revealed the potential of our multifunctional system for miRNA delivery and the demonstrated the therapeutic effectiveness against cancer cells, thereby providing a versatile all-in-one MOFs strategy for delivery of nucleic acids and diverse therapeutic molecules in synergistic therapy.