Photogenetic‐Like Liposomes Disrupt Neuroligin‐3 Dependency to Enhance Glioma Treatment

Abstract Neuronal activity is shown to potentiate glioma initiation, progression, and/or metastasis. A key mechanism in neural regulation of brain cancer involves the activity‐dependent cleavage and release of the synaptic adhesion molecule neuroligin‐3 (NLGN3). Here, this report describes the preparation of optogenetics‐like liposome Lip‐CuRA, which is used to regulate the content of NLGN3 in neurons and mediate phototherapy in cancer cells. Lip‐CuRA contains upconversion nanoparticles encapsulating CuS (CuS@PUCNPs), a visible light‐activated neurotransmitter prodrug RuBi‐GABA, and a disintegrin and metalloproteinase (ADAM10) inhibitors GI254023X. Upon 980 nm laser irradiation, the photothermal conversion of CuS not only induces tumor cell apoptosis, but also destroys liposome structure, releasing Rubi‐GABA and GI254023X. The UCNPs convert the 980 nm laser into 540 nm, activating RuBi‐GABA into GABA. GABA selectively opens Cl⁻ 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‐luc orthotopic glioma model, C6‐luc orthotopic glioma model, and glioma patient‐derived xenograft (PDX) model, Lip‐CuRA effectively inhibits tumor recurrence, reduces glioma stemness, and extends survival through a synergistic photothermal and NLGN3‐regulating therapy.