Engineering Multifunctional Thylakoid as an Oxygen Self-Supplying Photosensitizer for Esophageal Squamous Cell Carcinoma-Targeted Photodynamic Therapy

Photodynamic therapy (PDT) has emerged as an alternative treatment strategy for esophageal squamous cell carcinoma (ESCC). However, the clinical therapeutic efficiency of PDT is severely limited by poorly targeted photosensitizer delivery, insufficient oxygen supply, and neutralization by excessive glutathione (GSH) in tumor tissue. Herein, an engineered multifunctional thylakoid nanostructure, TMEM@ PLGA@GA (abbreviated as TEPG), composed of a thylakoid membrane (TM) and ESCC cell membrane (EM)-fused biomembrane (TM-EM) shell and gambogic acid (GA)-loaded poly (lactic-co-glycolic acid) nanocore, was designed for enhanced PDT for ESCC. When fused with EM, TM-EM exhibits a tumor targeting advantage due to the homologous affinity of tumor membrane camouflage. The catalase present on TM-EM catalytically decomposes endogenous hydrogen peroxide into oxygen to alleviate hypoxia in the tumor tissue. Moreover, when TEPG was selectively internalized by ESCC cells, GA was released to consume the excessive intracellular GSH. Under infrared irradiation, the PDT effects were enhanced by the self-oxygen supply and GSH scavenging ability provided by TEPG. An in vivo study showed that TEPG effectively induced ESCC tumor cell apoptosis and greatly inhibited the growth of ESCC tumors under infrared irradiation. This study constructed an engineered multifunctional thylakoid-based nanomedicine as an integrated solution to enhance PDT for ESCC.