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Siglec15, a newly discovered immune checkpoint, has been reported to repress immune responses in the tumor microenvironment (TME) and regulate osteoclast differentiation. However, the role of Siglec15 in the treatment for bone metastasis remains unclear. Herein, Siglec15 shows significantly higher expression in lung adenocarcinoma spinal metastasis (LUAD\u2010SM) than in para\u2010cancerous spinal tissues and primary LUAD. Subsequently, a TME\u2010responsive hollow MnO<jats:sub>2<\/jats:sub> nanoplatform (H\u2010M) loaded with Siglec15 siRNA and cisplatin (H\u2010M@siS15\/Cis) is developed, and the surface is modified with an aspartic acid octapeptide (Asp<jats:sup>8<\/jats:sup>), thus allowing H\u2010M to target spinal metastasis. High drug\u2010loading capacity, good biocompatibility, effective tumor accumulation, and efficient Siglec15 silencing are demonstrated. Furthermore, the nanoparticles could reverse immunosuppression caused by tumor cells and tumor\u2010associated macrophages (TAMs) and inhibit osteoclast differentiation via Siglec15 downregulation in vitro. In a LUAD\u2010SM mouse model, H\u2010M@siS15\/Cis\u2010Asp<jats:sup>8<\/jats:sup> exhibits superior therapeutic efficacy via synergetic immunochemotherapy and osteolysis inhibition. Taken together, this single nanoplatform reveals the therapeutic potential of the new immune checkpoint Siglec15 in LUAD\u2010SM and provides a strategy to treat this disease.<\/jats:p>","DOI":"10.1002\/smll.202107787","type":"journal-article","created":{"date-parts":[[2022,6,25]],"date-time":"2022-06-25T07:55:00Z","timestamp":1656143700000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Siglec15 Checkpoint Blockade for Simultaneous Immunochemotherapy and Osteolysis Inhibition in Lung Adenocarcinoma Spinal Metastasis via a Hollow Nanoplatform"],"prefix":"10.1002","volume":"18","author":[{"given":"Haifeng","family":"Liang","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery Zhongshan Hospital Fudan University  Shanghai 200032 China"},{"name":"Cancer Center Zhongshan Hospital Fudan University  Shanghai 200032 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Zhongshan Hospital Fudan University  Shanghai 200032 China"},{"name":"Cancer Center Zhongshan Hospital Fudan University  Shanghai 200032 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhichao","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Zhongshan Hospital Fudan University  Shanghai 200032 China"},{"name":"Cancer Center Zhongshan Hospital Fudan University  Shanghai 200032 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxiang","family":"Ge","sequence":"additional","affiliation":[{"name":"Department of Orthopedics Surgery Minhang Hospital Fudan University  Shanghai 201100 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taiwei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Zhongshan Hospital Fudan University  Shanghai 200032 China"},{"name":"Cancer Center Zhongshan Hospital Fudan University  Shanghai 200032 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Zhongshan Hospital Fudan University  Shanghai 200032 China"},{"name":"Cancer Center Zhongshan Hospital Fudan University  Shanghai 200032 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Zhongshan Hospital Fudan University  Shanghai 200032 China"},{"name":"Cancer Center Zhongshan Hospital Fudan University  Shanghai 200032 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunyi","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Zhongshan Hospital Fudan University  Shanghai 200032 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wang","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Orthopedics Surgery Minhang Hospital Fudan University  Shanghai 201100 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Zhongshan Hospital Fudan University  Shanghai 200032 China"},{"name":"Cancer Center Zhongshan Hospital Fudan University  Shanghai 200032 China"},{"name":"Department of Orthopaedic Surgery Zhongshan Hospital Wusong Branch Fudan University  Shanghai 200940 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengfeng","family":"Xue","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Molecular Imaging Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital Shanghai University of Medicine and Health Sciences  Shanghai 201318 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5082-1849","authenticated-orcid":false,"given":"Libo","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Zhongshan Hospital Fudan University  Shanghai 200032 China"},{"name":"Cancer Center Zhongshan Hospital Fudan University  Shanghai 200032 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,6,25]]},"reference":[{"key":"e_1_2_8_1_1","first-page":"5542","volume-title":"Clin. 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