Polyamine-activated carbonyl stress strategy for oxidative damage therapy

Abstract Oxidative damage, which mainly includes cell membrane lipid peroxidation (LPO) and DNA damage, plays a vital role in tumor therapy. Unfortunately, the overproduction of polyamines in tumor tissues inhibits cell membrane LPO and promotes DNA repair, leading to the limited oxidative damage efficacy. Herein, we propose an innovative polyamine-activated carbonyl stress strategy based on the MIL-100 @PAO@PVP (MPP) nanoplatform that successfully overcomes the drawbacks of oxidative damage therapy and achieves excellent chemodynamic therapy (CDT)-induced oxidative damage efficacy. Once endocytozed by tumor cells, the loaded plasma amine oxidase (PAO) on MPP can rapidly deplete polyamines at the tumor site to produce a large amount of highly toxic acrolein and H2O2. The produced H2O2 enhances the MIL-100-driven CDT efficiency to promote cell membrane and DNA damage. Furthermore, the depletion of polyamines further reduces the stability of the cell membrane and DNA. More importantly, the reactive product, acrolein, induces carbonyl stress to further increase DNA damage, inhibit the expression of GPx4 and DNA repair proteins, and significantly enhance CDT-induced oxidative damage. Overall, this strategy not only efficiently overcomes the drawbacks of oxidative damage but also provides a new strategy for tumor treatment.