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Increasing evidence suggests that nanomedicine offers unique opportunities for the integrated management of RA-associated depression by enabling precise modulation of both peripheral inflammation and central nervous system (CNS) pathology. This review outlines the biological mechanisms linking RA and depression\u2014including cytokine cascades, mitochondrial dysfunction, reactive oxygen species (ROS) accumulation, and microbial metabolite imbalance\u2014and highlights recent progress in nanocarrier platforms capable of dual-site intervention. Liposomes, polymeric nanoparticles (NPs), exosomes, inorganic nanozymes, and emerging carbon-based nanomaterials have demonstrated the ability to target inflamed synovium, reprogram macrophage phenotypes, traverse the blood\u2013brain barrier (BBB), suppress microglial overactivation, enhance neuroplasticity, and restore gut microbial homeostasis. Furthermore, stimulus-responsive nanoplatforms activated by ROS, pH, enzymes, or hypoxia provide spatiotemporally controlled drug release, thereby improving therapeutic precision. Finally, we discuss integrative designs such as dual-targeting nanomedicines, co-delivery systems, and microbiota-modulating nano-interventions, which offer promising strategies for the comprehensive treatment of RA-associated depression. This review aims to provide mechanistic insights and design principles to guide the development of next-generation nanomedicine for coordinated systemic-central modulation in RA comorbidity.<\/jats:p>","DOI":"10.3390\/ph19010094","type":"journal-article","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T16:07:07Z","timestamp":1767629227000},"page":"94","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Nanomedicine-Driven Therapeutic Strategies for Rheumatoid Arthritis-Associated Depression: Mechanisms and Pharmacological Progress"],"prefix":"10.3390","volume":"19","author":[{"given":"Jiaxiang","family":"Hu","sequence":"first","affiliation":[{"name":"Jinghua Academy of Zhejiang Chinese Medicine University, Jinghua 321015, China"},{"name":"Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Neuropsychiatric Diseases, Yunnan University of Chinese Medicine, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9700-1549","authenticated-orcid":false,"given":"Mingqin","family":"Shi","sequence":"additional","affiliation":[{"name":"Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Neuropsychiatric Diseases, Yunnan University of Chinese Medicine, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"Tian","sequence":"additional","affiliation":[{"name":"Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Neuropsychiatric Diseases, Yunnan University of Chinese Medicine, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baiqing","family":"Xie","sequence":"additional","affiliation":[{"name":"Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Neuropsychiatric Diseases, Yunnan University of Chinese Medicine, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Tan","sequence":"additional","affiliation":[{"name":"Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Neuropsychiatric Diseases, Yunnan University of Chinese Medicine, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongxu","family":"Zhou","sequence":"additional","affiliation":[{"name":"Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Neuropsychiatric Diseases, Yunnan University of Chinese Medicine, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tengfei","family":"Qian","sequence":"additional","affiliation":[{"name":"The People\u2019s Hospital of Mengzi, The Affiliated Hospital of Yunnan University of Chinese Medicine, Mengzi 661100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2005-8408","authenticated-orcid":false,"given":"Dongdong","family":"Qin","sequence":"additional","affiliation":[{"name":"Jinghua Academy of Zhejiang Chinese Medicine University, Jinghua 321015, China"},{"name":"Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Neuropsychiatric Diseases, Yunnan University of Chinese Medicine, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1038\/s41584-023-01037-w","article-title":"Immune Mechanisms of Depression in Rheumatoid Arthritis","volume":"19","author":"Brock","year":"2023","journal-title":"Nat. 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