A Metabolism-Oriented Strategy to Directly Generate Photosensitizer-Engineered Extracellular Vesicles from Cancer...

Area of Science:

• Biotechnology
• Nanomedicine
• Cancer Research

Background:

• Extracellular vesicles (EVs) show promise for cancer drug delivery but face challenges in efficient loading and production.
• Current methods for engineering EVs often involve complex procedures that limit their therapeutic application.

Purpose of the Study:

• To develop a novel, metabolism-driven strategy for efficient, in situ engineering of cancer cell-derived EVs loaded with a photosensitizer drug.
• To investigate the role of glucose metabolism in the production of engineered EVs.

Main Methods:

• Synthesized a glucose-conjugated photosensitizer (TBG) by modifying a photosensitizer (TB) with β-D-glucose.
• Co-incubated cancer cells with TBG, utilizing it as a metabolic substrate to engineer EVs.
• Analyzed EV yield and characteristics from TBG-treated cells compared to cells treated with the unconjugated photosensitizer (TB).
• Evaluated the efficacy of TBG-engineered EVs in photodynamic therapy for tumor ablation.

Main Results:

• Cancer cells directly produced TBG-engineered EVs in situ through a metabolism-driven process involving glucose transporters.
• TBG treatment resulted in a higher yield of engineered EVs compared to TB treatment, linked to increased glucose transporter activity and ATP synthesis.
• The metabolism-driven strategy was successfully validated across three cancer cell lines.
• TBG-engineered EVs demonstrated effective cancer cell targeting and enhanced efficacy in photodynamic therapy.

Conclusions:

• A novel, simple, and efficient method for producing cargo-loaded EVs using direct biological metabolism has been established.
• This metabolism-driven approach overcomes limitations of traditional EV engineering, offering a versatile strategy for cancer therapy.
• Glucose modification of therapeutic agents can enhance EV production and therapeutic outcomes.