Modulating Intracellular Autophagy and Macropinocytosis for Increased Neighboring Drug Delivery

Neighboring effects provided a valuable direction for in-depth penetration of nanoparticles into tumors. However, the uncontrollable drug transcytosis and limited drug uptake hindered by viscous cancer-associated fibroblasts (CAFs) greatly limit their in-depth penetration. Here, we proposed and demonstrated that intracellular autophagosomes could carry the remaining drugs to neighboring cells, and the enhanced macropinocytosis played a major role in neighboring delivery. To enhance the autophagosome-based neighboring delivery, Ca²⁺-doped polydopamine was prepared to load GLS1 inhibitor CB-839 and modified glutamine (839/CG) for triggering macropinocytosis-based active cells uptake. After Ca²⁺-release caused lysosome damage, 839/CG escaped from lysosomes and hindered the autophagosome maturation. Then, Ca²⁺-induced endoplasmic reticulum oscillations and glutamine starvation both increased and blocked autophagy flow, causing 839/CG-contained autophagosome accumulation. Meanwhile, the tumor increased its macropinocytosis in response to mTOR downregulation-induced glutamine hunger, causing "the more you eat, the hungrier you get". After tumor death, the 839/CG-contained autophagosomes were released and actively ingested by neighboring hungry tumor cells through macropinocytosis. Combined with the photothermal effect triggered CAF decrease, neighboring cells repeated the above process for in-depth tumor delivery. Also, immunogenic death enhanced the antigen presentation of DCs and infiltration of T cells, thereby inhibiting tumor growth and lung metastasis.