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A key mechanism in neural regulation of brain cancer involves the activity\u2010dependent cleavage and release of the synaptic adhesion molecule neuroligin\u20103 (NLGN3). Here, this report describes the preparation of optogenetics\u2010like liposome Lip\u2010CuRA, which is used to regulate the content of NLGN3 in neurons and mediate phototherapy in cancer cells. Lip\u2010CuRA contains upconversion nanoparticles encapsulating CuS (CuS@PUCNPs), a visible light\u2010activated neurotransmitter prodrug RuBi\u2010GABA, and a disintegrin and metalloproteinase (ADAM10) inhibitors GI254023X. Upon 980\u00a0nm laser irradiation, the photothermal conversion of CuS not only induces tumor cell apoptosis, but also destroys liposome structure, releasing Rubi\u2010GABA and GI254023X. The UCNPs convert the 980\u00a0nm laser into 540\u00a0nm, activating RuBi\u2010GABA into GABA. GABA selectively opens Cl\u207b channels in nerve cells, reducing the expression of NLGN3 and the degree of axonal connections. GI254023X inhibits the activity of the ADAM10 enzyme on the nerve surface, reducing the release of NLGN3, thereby blocking the transmission of proliferation and stemness signals. In the GL261\u2010luc orthotopic glioma model, C6\u2010luc orthotopic glioma model, and glioma patient\u2010derived xenograft (PDX) model, Lip\u2010CuRA effectively inhibits tumor recurrence, reduces glioma stemness, and extends survival through a synergistic photothermal and NLGN3\u2010regulating therapy.<\/jats:p>","DOI":"10.1002\/adma.202503631","type":"journal-article","created":{"date-parts":[[2025,5,6]],"date-time":"2025-05-06T03:59:34Z","timestamp":1746503974000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Photogenetic\u2010Like Liposomes Disrupt Neuroligin\u20103 Dependency to Enhance Glioma Treatment"],"prefix":"10.1002","volume":"37","author":[{"given":"Mengbin","family":"Ding","sequence":"first","affiliation":[{"name":"Academy of Medical Engineering and Translational Medicine Medical College Tianjin University  Tianjin 300072 China"},{"name":"State Key Laboratory of Advanced Medical Materials and 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