{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T22:56:46Z","timestamp":1791845806038,"version":"4.3.4"},"reference-count":61,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T00:00:00Z","timestamp":1780531200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Objective: This study aimed to develop an oral celastrol-loaded self-microemulsifying drug delivery system (Cel-SMEDDS) to enhance the therapeutic efficacy against rheumatoid arthritis and reduce toxicity. Methods: The optimal Cel-SMEDDS formulation, identified through solubility screening, excipient compatibility assays, and pseudo-ternary phase diagram analysis, was characterized by particle size, PDI, zeta potential, in vitro release, and stability. In vitro anti-inflammatory activity was evaluated in LPS-induced RAW264.7 macrophages, while in vivo anti-RA efficacy was assessed in CIA mice via paw swelling, clinical scoring, serum TNF-\u03b1, and joint histopathology. Preliminary safety was examined by hematological, serum biochemical, and histopathological analyses in mice. Results: The optimal Cel-SMEDDS formulation consisted of LABRAFIL M 1944 CS-Kolliphor RH40-CAPRYOL 90 (0.2:0.48:0.32, w\/w\/w) with a drug loading of 1.5% (w\/w). It spontaneously formed uniform microemulsions with a mean particle size of 26.70 nm, PDI of 0.067, and zeta potential of \u22122.87 mV. In vitro, Cel-SMEDDS showed enhanced cytotoxicity against M1-type macrophages (IC50 = 0.1753 \u03bcg\/mL vs. 0.2684 \u03bcg\/mL for free Cel), significantly suppressed pro-inflammatory TNF-\u03b1 and IL-1\u03b2 expression, and upregulated anti-inflammatory IL-10. In CIA mice, oral Cel-SMEDDS reduced paw swelling by 37.42% (vs. 22.79% for free Cel), markedly decreased serum and intra-articular TNF-\u03b1 levels, and alleviated articular cartilage damage. Preliminary safety evaluation demonstrated no significant abnormalities in hematological parameters, liver\/kidney function, or major organ histology. Conclusions: The optimized oral Cel-SMEDDS effectively inhibits the expression of pro-inflammatory cytokine TNF-\u03b1 both in vitro and in vivo, exhibits superior anti-RA activity compared to free Cel, and possesses favorable safety. This formulation addresses the key limitations of celastrol and shows promising potential for clinical translation in RA treatment.<\/jats:p>","DOI":"10.3390\/pharmaceutics18060695","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T03:24:33Z","timestamp":1780629873000},"page":"695","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Orally Administered Self-Microemulsifying Celastrol Alleviates Rheumatoid Arthritis by Modulating the Expression of TNF-\u03b1"],"prefix":"10.3390","volume":"18","author":[{"given":"Boqin","family":"Ma","sequence":"first","affiliation":[{"name":"School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Li","sequence":"additional","affiliation":[{"name":"Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai 264000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahui","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Yantai University, Yantai 264005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanlei","family":"Fu","sequence":"additional","affiliation":[{"name":"Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai 264000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiqiang","family":"Cao","sequence":"additional","affiliation":[{"name":"Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e32","DOI":"10.1056\/NEJMp2310178","article-title":"What Is Rheumatoid Arthritis?","volume":"390","author":"Gravallese","year":"2024","journal-title":"N. 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