A Metabolism‐Oriented Strategy to Directly Generate Photosensitizer‐Engineered Extracellular Vesicles from Cancer Cells

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.