{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T12:53:23Z","timestamp":1791204803553,"version":"4.1.0"},"reference-count":115,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Rheumatoid arthritis (RA), systemic lupus erythematosus\/lupus nephritis (SLE\/LN), and systemic sclerosis (SSc) remain major causes of chronic inflammation, disability, organ damage, and treatment burden despite therapeutic advances. RNA therapeutics offer programmable transcript suppression, network-level microRNA modulation, transient restoration of protective proteins, and targeting-ligand functions. Existing reviews largely catalogue modalities or individual delivery systems; this review instead asks whether a candidate forms an interpretable translational program across target biology, disease compartment, intended cell, productive intracellular access, direct target engagement, pathway pharmacodynamics, repeat-dose safety, and manufacturing feasibility. RA is primarily a synovial immune\u2013stromal delivery problem in which RNA programs must also demonstrate an advantage over effective biologic or targeted synthetic therapies. SLE\/LN offers interferon, B-cell, co-stimulatory, microRNA, messenger RNA (mRNA), and complement opportunities, but therapeutic nucleic acids and carriers must not intensify nucleic-acid sensing, interferon activity, or complement-associated injury. SSc combines strong antifibrotic RNA biology with an accessible skin proof-of-mechanism window, whereas lung, vascular, and internal-organ programs remain more delivery-limited. We separate human pathway validation, RNA-platform evidence outside the target disease, disease-specific RNA evidence, and patient efficacy. Recent human complement-factor-B pharmacodynamic data strengthen the platform-level evidence but do not establish efficacy in RA or LN. The most informative early trials will therefore be biomarker-enriched and mechanism-rich, with prespecified criteria that distinguish target failure from delivery, dose, endotype, or safety failure.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1950465","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T12:16:53Z","timestamp":1791202613000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["RNA therapeutics in rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis: a compartment-aware translational framework"],"prefix":"10.3389","volume":"17","author":[{"given":"Yusif","family":"Afandizada","sequence":"first","affiliation":[{"name":"NOBELab (Nucleosides, Oligonucleotides, and Biological Evaluation Laboratory), Division of Basic Medical Sciences, Faculty of Medicine and Health Sciences, Qaraba\u011f University","place":["Khankendi, Azerbaijan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hikmet","family":"Memmedov","sequence":"additional","affiliation":[{"name":"Division of Basic Medical Sciences, Faculty of Medicine and Health Sciences, Qaraba\u011f University","place":["Khankendi, Azerbaijan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mushfig","family":"Orujov","sequence":"additional","affiliation":[{"name":"Division of Basic Medical Sciences, Faculty of Medicine and Health Sciences, Qaraba\u011f University","place":["Khankendi, Azerbaijan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahla","family":"Eyvazova","sequence":"additional","affiliation":[{"name":"Division of Basic Medical Sciences, Faculty of Medicine and Health Sciences, Qaraba\u011f University","place":["Khankendi, Azerbaijan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shirkhan","family":"Amikishiyev","sequence":"additional","affiliation":[{"name":"Division of 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