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A 15\u2010mer synthetic anti\u2010inflammatory peptide (SAP15) was designed from human \u03b2\u2010defensin 3 to penetrate cells and induce intracellular downregulation of inflammation. The downregulation of inflammation was achieved by the binding of SAP15 to intracellular histone deacetylase (HDAC5). SAP15\u2010mediated inhibition of inflammation was examined in vitro and in vivo using murine macrophages, human articular chondrocytes, and a collagen\u2010induced arthritis (CIA) rat model. Surface plasmon resonance and immunoprecipitation assays indicated that SAP15 binds to HDAC5. SAP15 inhibited the lipopolysaccharide (LPS)\u2010induced phosphorylation of intracellular HDAC5 and NF\u2010\u03baB p65 in murine macrophages. SAP15 treatment increased aggrecan and type II collagen expression and decreased osteocalcin expression in LPS\u2010induced chondrocytes. Subcutaneous injection of SAP15\u2010loaded sodium hyaluronic acid (HA) solution significantly decreased hind paw swelling, joint inflammation, and serum cytokine levels in CIA rats compared with the effects of sodium HA solution alone. The SAP15\u2010loaded HA group exhibited preservation of cartilage and bone structure in CIA rat joints. Moreover, a more robust anti\u2010inflammatory effect of the SAP15 loaded HA was observed than that of etanercept (an anti\u2010tumor necrosis factor\u2010alpha [TNF\u2010\u03b1] antibody)\u2010loaded HA. These findings suggest that SAP15 has an anti\u2010inflammatory effect that is not controlled by sodium HA and is mediated by inhibiting HDAC5, unlike the anti\u2010inflammatory mechanism of etanercept. These results demonstrate that SAP15 is useful as an inflammatory regulator of biomaterials and can be developed as a therapeutic for the treatment of inflammation.<\/jats:p>","DOI":"10.1002\/jbm.a.37192","type":"journal-article","created":{"date-parts":[[2021,4,5]],"date-time":"2021-04-05T09:14:39Z","timestamp":1617614079000},"page":"2001-2016","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Engineered synthetic cell penetrating peptide with intracellular anti\u2010inflammatory bioactivity: An in vitro and in vivo study"],"prefix":"10.1002","volume":"109","author":[{"given":"Jue\u2010Yeon","family":"Lee","sequence":"first","affiliation":[{"name":"Research Institute Nano Intelligent Biomedical Engineering Corporation (NIBEC)  Seoul Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dong Woo","family":"Lee","sequence":"additional","affiliation":[{"name":"Research Institute Nano 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