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Here, we present a programmed nanovesicle to sequentially overcome biological barriers and rewire the immune landscape of GBM. The system integrates genetically engineered cytomembrane vesicles displaying a matrix metalloproteinase-responsive Ang2-CD47 nanobody fusion with sono-activatable albumin nanocages coencapsulating a CD73 inhibitor (APCP) and an organic sonosensitizer. Ang2-mediated engagement of low-density lipoprotein receptor-related protein 1 enables blood\u2013brain barrier translocation, whereas proteolytic shedding of the Ang2 corona within the tumor milieu promotes intratumoral retention and unmasks the CD47 nanobody to block the CD47-SIRP\u03b1 phagocytosis checkpoint. Upon sono-irradiation, the nanovesicle induces sonodynamic cytotoxicity and immunogenic cell death, while triggering self-dissociation for on-demand APCP release. The released APCP further suppresses the CD73-adenosine axis, rescuing effector immune cells from adenosine-mediated dysfunction. These coordinated processes establish a self-reinforcing immune cascade that reprograms GBM into an immunologically permissive niche. Notably, the sonosensitizer possesses NIR-II photoacoustic activity, enabling high-resolution imaging of deep-seated tumors. This nanovesicle elicits durable antitumor efficacy and robust immune remodeling in aggressive and recurrent orthotopic GBM models, offering a promising paradigm for dismantling immunotherapeutic resistance in malignant brain tumors.<\/jats:p>","DOI":"10.1021\/jacs.6c13917","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T11:02:14Z","timestamp":1791198134000},"page":"43566-43586","source":"Crossref","is-referenced-by-count":0,"title":["Activatable\nNanovesicle Rewires Immunometabolic Barriers\nfor NIR-II Photoacoustic-Guided Sono-immunotherapy of Glioblastoma"],"prefix":"10.1021","volume":"148","author":[{"given":"Mengyun","family":"Liang","sequence":"first","affiliation":[{"name":"Nankai University , , ,","place":["Tianjin, China, 300071"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongyou","family":"Tao","sequence":"additional","affiliation":[{"name":"Nankai University , , ,","place":["Tianjin, China, 300071"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanwen","family":"Liu","sequence":"additional","affiliation":[{"name":"Nankai University , , ,","place":["Tianjin, China, 300071"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueping","family":"Li","sequence":"additional","affiliation":[{"name":"Chinese Academy of Medical Sciences and Peking Union Medical College , , ,","place":["Tianjin, China, 300192"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Nankai University , , ,","place":["Tianjin, China, 300071"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Chinese Academy of Medical Sciences and Peking Union Medical College , , ,","place":["Tianjin, China, 300192"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianwen","family":"Song","sequence":"additional","affiliation":[{"name":"Nankai University , , ,","place":["Tianjin, China, 300071"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengjie","family":"Ye","sequence":"additional","affiliation":[{"name":"Nankai University , , ,","place":["Tianjin, China, 300071"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ershuang","family":"Li","sequence":"additional","affiliation":[{"name":"Nankai University , , ,","place":["Tianjin, China, 300071"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6783-1464","authenticated-orcid":true,"given":"Wen","family":"Li","sequence":"additional","affiliation":[{"name":"Chinese Academy of Medical Sciences and Peking Union Medical College , , ,","place":["Tianjin, China, 300192"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7597-9725","authenticated-orcid":true,"given":"Ji","family":"Qi","sequence":"additional","affiliation":[{"name":"Nankai University , , ,","place":["Tianjin, China, 300071"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,10,5]]},"reference":[{"key":"2026101414071546100_cit1","doi-asserted-by":"publisher","first-page":"v1","DOI":"10.1093\/neuonc\/noac202","article-title":"CBTRUS Statistical report:\nprimary brain and other central nervous\nsystem tumors diagnosed in the United States in 2015\u20132019","volume":"24","author":"Ostrom","year":"2022","journal-title":"Neuro-Oncol."},{"key":"2026101414071546100_cit2","doi-asserted-by":"publisher","first-page":"299","DOI":"10.3322\/caac.21613","article-title":"Management of glioblastoma: State of the art and future directions","volume":"70","author":"Tan","year":"2020","journal-title":"Ca-Cancer J. 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