{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T08:56:46Z","timestamp":1776329806277,"version":"3.50.1"},"reference-count":43,"publisher":"American Association for the Advancement of Science (AAAS)","funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82372415"],"award-info":[{"award-number":["82372415"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021171","name":"Guangdong Basic and Applied Basic Research Foundation","doi-asserted-by":"crossref","award":["2023A1515111096"],"award-info":[{"award-number":["2023A1515111096"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"crossref"}]},{"name":"The Research Foundation of Medical Science and Technology of Guangdong Province","award":["A2024315"],"award-info":[{"award-number":["A2024315"]}]},{"name":"The Chinese Traditional Medicine Foundation of Guangdong Province","award":["20261425"],"award-info":[{"award-number":["20261425"]}]}],"content-domain":{"domain":["spj.science.org"],"crossmark-restriction":true},"short-container-title":["Biomater Res"],"published-print":{"date-parts":[[2026,1,1]]},"abstract":"<jats:p>Aseptic loosening (AL) represents the primary cause of joint arthroplasty failure, which is predominantly triggered by chronic inflammatory reactions to prosthetic wear particles, with macrophages serving as the central effector cells. Accumulating evidence indicates that the crosstalk between endoplasmic reticulum stress and mitochondrial stress exacerbates macrophage-mediated inflammation; however, the core molecular regulators orchestrating this pathological cascade remain elusive. Herein, we investigated the functional role of the GATA6\/DDX3X (DEAD-box helicase 3 X-linked) axis in titanium particle (TiP)-induced macrophage inflammatory responses and further explored the therapeutic potential of nanoparticle-loaded injectable hydrogels for AL. Specifically, a si-DDX3X-loaded nanoparticle hydrogel (si-DDX3X NPs@Hy) was fabricated and characterized, and its therapeutic efficacy was evaluated in\u00a0vivo. Our results demonstrated that DDX3X expression was significantly up-regulated in both TiP-stimulated bone marrow-derived macrophages and periprosthetic tissues obtained from AL patients. Functional assays revealed that DDX3X promoted mitochondria\u2013endoplasmic reticulum interplay, which in turn facilitated NLRP3 inflammasome assembly and subsequent interleukin-1\u03b2 secretion. Mechanistically, GATA6 directly bound to the transcription start site of the DDX3X gene, thereby suppressing its transcriptional expression and abrogating DDX3X-mediated proinflammatory effects. The synthesized si-DDX3X NPs@Hy exhibited favorable physicochemical properties; local administration of this hydrogel markedly attenuated TiP-induced calvarial osteolysis in mice, accompanied by reduced osteoclastogenesis, proinflammatory cytokine production, and M1 macrophage polarization in the lesion microenvironment. Collectively, this study identifies the GATA6\/DDX3X axis as a pivotal regulator of TiP-driven macrophage inflammation and validates the si-DDX3X NPs@Hy as a promising therapeutic strategy for targeting wear particle-induced inflammation, which holds great potential for improving the long-term prognosis of joint arthroplasty.<\/jats:p>","DOI":"10.34133\/bmr.0353","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T08:15:54Z","timestamp":1774426554000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":0,"title":["Nanoparticle-Loaded Injectable Hydrogel Alleviates Titanium Particle-Induced Osteolysis by Disrupting GATA6\/DDX3X-Mediated Macrophage Inflammation"],"prefix":"10.34133","volume":"30","author":[{"given":"Sipeng","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Orthopedics, Shenshan Medical Center, Sun Yat-sen Memorial Hospital, \rSun Yat-sen University, Shanwei, Guangdong 516621, P. R. China."},{"name":"Department of Orthopedic Surgery, Sun Yat-sen Memorial Hospital, \rSun Yat-sen University, Guangzhou, Guangdong 510000, P. R. China."},{"name":"Guangdong Provincial Key Laboratory of Cancer Pathogenesis and Precision Diagnosis and Treatment","place":["P. R. China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taihe","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Sun Yat-sen Memorial Hospital, \rSun Yat-sen University, Guangzhou, Guangdong 510000, P. R. China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qi","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Shenshan Medical Center, Sun Yat-sen Memorial Hospital, \rSun Yat-sen University, Shanwei, Guangdong 516621, P. R. 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