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It lacks effective treatment due to the complex pathogenesis. Gene therapy, especially targeted oligonucleotide (ON) delivery therapy, offers a new prospect for the precise treatment of RA. Nevertheless, the clinical application of ON delivery therapy still faces various challenges such as the rapid enzymolysis by RNAse, the lack of tissue targeting ability, difficulty in cell membrane penetration, and the incapability of endolysosomal escape. To address these issues, a novel kind of engineered peptide and oligonucleotide (PON) nanohybrids are designed and fabricated, which provide various advantages including good biosafety, inflammatory region\u2010targeted delivery, cell membrane penetration, reactive oxygen species (ROS) scavenging, and endolysosomal escape. The PON nanohybrids produce promising effects in suppressing inflammatory responses and osteoclastogenesis of macrophages via multiple signaling pathways. In vivo administration of PON nanohybrids not only ameliorates local joint bone destruction and systemic osteoporosis in the pathological state, but also demonstrates good prophylactic effects against the rapid progression of RA disease. In conclusion, the study presents a promising strategy for precise RA treatment and broadens the biomedical applications of gene therapy based on delivery system.<\/jats:p>","DOI":"10.1002\/adma.202500883","type":"journal-article","created":{"date-parts":[[2025,3,19]],"date-time":"2025-03-19T03:52:02Z","timestamp":1742356322000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Peptide\u2010Oligonucleotide Nanohybrids Designed for Precise Gene Therapy of Rheumatoid Arthritis"],"prefix":"10.1002","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-7455-1343","authenticated-orcid":false,"given":"Qing","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Orthopedics The First Affiliated Hospital of Soochow University  Suzhou Jiangsu 215006 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