Tumor microenvironment responsive smart nanoplatform for synergistic tumor therapy through co-enhancement of GSH depletion and hypoxia relief.

As innovative therapeutic strategy, chemodynamic therapy (CDT) and photodynamic therapy (PDT) show great promise for tumor therapy. However, their therapeutic efficacy is seriously limited by the hypoxia and insufficient H2O2 supply of the tumor microenvironment. Juglone (JUG), a naturally-occurring naphthoquinone, can increase the intracellular H2O2 concentration and serve as an inhibitor of peptidyl-prolyl cis-trans isomerase NIMA-interacting 1. Herein, a nanoplatform composed of Fe-based metal-organic framework core, MnO2 layer, JUG payload, and hyaluronic acid (HA) decoration (Fe-TCPP@MnO2@JUG@HA) was designed and prepared. The MnO2 layer can prevent the phototoxicity of tetrakis (4-carboxyphenyl)porphyrin (TCPP) during transportation and catalyze H2O2 to produce O2 to enhance the PDT efficacy. HA can improve the delivery efficiency to tumor. Then Fe3+ was reduced to Fe2+ and MnO2 was reduced to Mn2+ because of the weak acidity and high concentration glutathione (GSH), causing the nanoplatform collapse, TCPP activation, and JUG release. GSH-depletion reduce the reactive oxygen species (ROS) scavenging effect and further enhance the PDT efficacy, inhibited the biosynthesis of lipid repair enzyme glutathione peroxidase 4 and promoted the ferroptosis efficiency by destroying redox balance. This PDT/CDT/chemotherapy triple synergistic apoptosis-ferroptosis strategy exhibited good tumor therapeutic efficacy and excellent biocompatibility, implying the promising future for efficient tumor treatment.