{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T16:00:16Z","timestamp":1770134416038,"version":"3.49.0"},"reference-count":35,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T00:00:00Z","timestamp":1761004800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T00:00:00Z","timestamp":1761004800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Adv Healthcare Materials"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Cellular senescence impairs clathrin\u2010mediated endocytosis (CME), partly due to reduced membrane fluidity and disrupted lipid raft composition, which hinder receptor clustering and limit drug uptake. To overcome this, a urokinase receptor (\u00b5PAR) antibody\u2010modified cationic liposome was developed loaded with plasmid of DNA\u2010repairing enzyme Sirt6 (anti\u2010\u00b5PAR@Lipo\u2010Sirt6), targeting the overexpressed \u00b5PAR on senescent chondrocytes to promote receptor clustering and enhance CME. Compared to Lipo\u2010Sirt6, anti\u2010\u00b5PAR@Lipo\u2010Sirt6 induced \u00b5PAR clustering and enhanced cellular uptake via the CME pathway. The results showed 1.7\u20132\u2010fold higher uptake efficiency in vitro and 1.5\u2010fold higher in vivo, leading to improved Sirt6 gene delivery. In vitro, treatment with anti\u2010\u00b5PAR@Lipo\u2010Sirt6 promoted DNA damage repair, significantly reduced the expression of senescence markers cyclin dependent kinase inhibitor 1a (Cdkn1a) and cyclin dependent kinase inhibitor 2a (Cdkn2a), and restored the expression of cartilage functional molecules type II collagen (Col2) and aggrecan (Acan). Encapsulation within hyaluronic acid\u2010methacrylate (HAMA) hydrogel microspheres (anti\u2010\u00b5PAR@Lipo\u2010Sirt6@HMs) further prolonged retention and efficacy in vivo, significantly reducing p53 expression, preserving cartilage matrix molecules such as Col2 and Acan, delaying cartilage degradation, and restoring gait function in osteoarthritis (OA) mice. This study demonstrates that receptor clustering can be harnessed to enhance drug uptake in senescent cells, offering a promising strategy for anti\u2010senescence therapy.<\/jats:p>","DOI":"10.1002\/adhm.202504034","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T18:17:05Z","timestamp":1761070625000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Remodeling Cellular Uptake via Inducing Clustering of Urokinase Receptors in Hydrogel Microspheres for Alleviating Cartilage Senescence"],"prefix":"10.1002","volume":"15","author":[{"given":"Zhiqi","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Sports Medicine Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  600 Yishan Road Shanghai 200000 P. R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenliang","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Sports Medicine Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  600 Yishan Road Shanghai 200000 P. R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yawei","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases Shanghai Institute of Traumatology and Orthopaedics Ruijin Hospital Shanghai Jiao Tong University School of Medicine  197 Ruijin 2nd Road Shanghai 200025 P. R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ding","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases Shanghai Institute of Traumatology and Orthopaedics Ruijin Hospital Shanghai Jiao Tong University School of Medicine  197 Ruijin 2nd Road Shanghai 200025 P. R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yihan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases Shanghai Institute of Traumatology and Orthopaedics Ruijin Hospital Shanghai Jiao Tong University School of Medicine  197 Ruijin 2nd Road Shanghai 200025 P. R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liren","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Sports Medicine Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  600 Yishan Road Shanghai 200000 P. R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuhao","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Sports Medicine Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  600 Yishan Road Shanghai 200000 P. R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ziyun","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Sports Medicine Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  600 Yishan Road Shanghai 200000 P. R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rongtai","family":"Zuo","sequence":"additional","affiliation":[{"name":"Department of Sports Medicine Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  600 Yishan Road Shanghai 200000 P. R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenguo","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases Shanghai Institute of Traumatology and Orthopaedics Ruijin Hospital Shanghai Jiao Tong University School of Medicine  197 Ruijin 2nd Road Shanghai 200025 P. R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2265-1878","authenticated-orcid":false,"given":"Jinzhong","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Sports Medicine Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  600 Yishan Road Shanghai 200000 P. R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,10,21]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.34133\/research.0612"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/SMMD.20230030"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s42765-024-00451-3"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/EXP.20220090"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhazmat.2021.126092"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2017.132"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jpcb.1c05403"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.249318"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.285.5425.221"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-022-00531-5"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1124\/pharmrev.122.000622"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/EXP.20220132"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.engreg.2020.08.002"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-32552-1"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvs017"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.12.5.1467"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-35424-w"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/smll.202400598"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/adbi.202300331"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2021.101332"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.15848"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aay3909"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-024-01889-y"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(02)03187-3"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/cpr.13167"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.78.081307.110540"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2019.07.017"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.34133\/research.0148"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111736200"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1165\/ajrcmb.24.1.3992"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21103498"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202203800"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.800481"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.671"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(16)30030-4"}],"container-title":["Advanced Healthcare Materials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/adhm.202504034","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/adhm.202504034","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/adhm.202504034","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T04:57:21Z","timestamp":1770094641000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/adhm.202504034"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,21]]},"references-count":35,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,2]]}},"alternative-id":["10.1002\/adhm.202504034"],"URL":"https:\/\/doi.org\/10.1002\/adhm.202504034","archive":["Portico"],"relation":{},"ISSN":["2192-2640","2192-2659"],"issn-type":[{"value":"2192-2640","type":"print"},{"value":"2192-2659","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,21]]},"assertion":[{"value":"2025-09-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-21","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e04034"}}