Extracellular vesicles (EVs) hold great potential for delivering cancer therapy drugs. However, limited efficiency and sophisticated drug encapsulation procedures have hindered their effectiveness. Herein, β-D-glucose is modified with the synthesized photosensitizer (1-(4-carboxybutyl)-4-(7-(4-(diphenylamino)phenyl)benzo[c][1,2,5] thiadiazol-4-yl)pyridin-1-ium, named TB) via amide bond to form a glucose-conjugated photosensitizer, referred to as TBG, which is further utilized as a metabolic substrate for cancer cells. Through simple co-incubation with TBG, cancer cells directly generate TBG-engineered EVs in situ via a metabolism-driven process, in which glucose transporters play a critical role. Notably, a higher yield of engineered EVs is observed in TBG-treated cells compared to the TB-treated group. This enhancement could be attributed to increased glucose transporter activity and adenosine triphosphate (ATP) synthesis, highlighting the significance of glucose-modified chemicals. Remarkably, this metabolism-driven strategy has been successfully validated across three cell lines, highlighting its versatility and broad applicability. The extracted TBG-EVs maintain a strong targeting ability toward cancer cells and demonstrate enhanced efficacy in photodynamic therapy for tumor ablation. The study offers an alternative strategy to efficiently produce cargo-loading EVs via direct biological metabolism.

中文翻译：

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一种以代谢为导向的策略，可从癌细胞直接生成光敏剂工程的细胞外囊泡

细胞外囊泡 （EV） 在递送癌症治疗药物方面具有巨大潜力。然而，有限的效率和复杂的药物包埋程序阻碍了其有效性。本文用合成的光敏剂（1-（4-羧基丁基）-4-（7-（4-（二苯氨基）苯基）苯并[c][1,2,5]噻二唑-4-基）吡啶-1-铉通过酰胺键修饰β-D-葡萄糖形成葡萄糖共轭光敏剂，称为 TBG，进一步用作癌细胞的代谢底物。通过与 TBG 的简单共孵育，癌细胞通过新陈代谢驱动的过程直接原位产生 TBG 工程的 EV，其中葡萄糖转运蛋白起着关键作用。值得注意的是，与 TB 处理组相比，在 TBG 处理的细胞中观察到工程化 EV 的产量更高。这种增强可归因于葡萄糖转运蛋白活性和三磷酸腺苷 （ATP） 合成的增加，突出了葡萄糖修饰化学物质的重要性。值得注意的是，这种代谢驱动的策略已在三种细胞系中成功验证，凸显了其多功能性和广泛适用性。提取的 TBG-EVs 对癌细胞保持了很强的靶向能力，并在光动力疗法中表现出增强的肿瘤消融疗效。该研究提供了一种通过直接生物代谢有效生产载货 EV 的替代策略。