Modulating Intracellular Autophagy and Macropinocytosis for Increased Neighboring Drug Delivery

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Therapy

Background:

• Nanoparticle drug delivery faces challenges in deep tumor penetration due to cancer-associated fibroblasts (CAFs).
• Uncontrolled drug transcytosis and limited uptake by CAFs hinder effective tumor targeting.

Purpose of the Study:

• To develop a novel strategy for enhanced in-depth tumor drug delivery using intracellular autophagosomes and macropinocytosis.
• To investigate the role of Ca2+-doped polydopamine nanoparticles loaded with a GLS1 inhibitor (CB-839) and glutamine (839/CG) in triggering this delivery mechanism.

Main Methods:

• Preparation of Ca2+-doped polydopamine nanoparticles loaded with CB-839 and glutamine (839/CG).
• Induction of lysosome damage and autophagy accumulation using 839/CG and Ca2+ release.
• Stimulation of tumor macropinocytosis via mTOR downregulation and glutamine starvation.
• Combination therapy with photothermal effect to reduce CAFs and promote repeated drug delivery cycles.

Main Results:

• 839/CG nanoparticles effectively triggered autophagosome accumulation and enhanced macropinocytosis in tumor cells.
• Released autophagosomes containing 839/CG were actively ingested by neighboring tumor cells, facilitating deep tumor penetration.
• Photothermal therapy reduced CAFs, enabling repeated cycles of drug delivery.
• The treatment induced immunogenic cell death, enhancing anti-tumor immune responses and reducing metastasis.

Conclusions:

• Intracellular autophagosomes combined with enhanced macropinocytosis represent a promising approach for deep tumor drug delivery.
• The developed 839/CG nanoparticles effectively exploit cellular mechanisms for targeted drug release and uptake.
• This strategy holds potential for improving cancer therapy efficacy by overcoming penetration barriers and enhancing immune responses.