A “pursuit and interception” strategy of amplified autophagy inhibition for tumor therapy based on ultra-small Rh nanoparticles

Abstract

Autophagy inhibition can limit the growth of established tumors and improve the response to tumor therapeutics. However, in complex dynamic process of catabolic lysosomal degradation, a single specific inhibition of autophagy results in limited effect. Here, we prepared ultra-small rhodium-methoxypolyethylene glycol-S-Nitrosothiols nanoparticles (uRh-mSNO NPs) to realize amplified autophagy inhibition effect through a “pursuit and interception” (as the game of “Go”) strategy for tumor therapy. In detail, uRh NPs were used to catalyze the generation of highly oxidizing hydroxyl radicals within tumor cells as peroxidase mimic, while –SNO was applied to produce the nitric oxide (NO) radicals under NIR irradiation, thus collectively triggering free radical cascade reaction to produce GSNO and H+. On one hand, GSNO could inhibit LC3B pathway to reduce the conversion of isolation membrane, therefore performing “pursuit” strategy to decrease the formation of phagophore. On the other hand, H+ would cause lysosome dysfunction to hinder the fusion process of autophagosomes with lysosome, thereby acting as “intercept” role to block the formation of autolysosome. Both in vitro and in vivo results evidenced the amplified autophagy inhibition effect based on uRh-mSNO NPs, which provided an informative strategy to future design of therapeutic regimen.