Polymorphic reactive oxygen species (ROS) storm for enhanced tumor therapy

Abstract Generating excessively reactive oxygen species (ROS) within tumor cells is a widely adopted therapeutic strategy. However, single‐type ROS exhibit fixed attack sites and mechanisms of action in tumor cells, rendering them susceptible to resistance via cellular repair mechanisms. To overcome this limitation, this study proposes a polymorphic ROS strategy that simultaneously induces multiple types of ROS to enhance the therapeutic efficacy. A nanoplatform named as AuPd@Mn x O y /L/DOX (AP‐M@L/D) is developed. AuPd core can catalyze oxygen to generate superoxide anions (O 2 · − ), and the released multivalent manganese ions in tumor can trigger the production of singlet oxygen ( 1 O 2 ) and hydroxyl radicals (·OH). The polymorphic ROS (O 2 · − , 1 O 2 , ·OH) with different reactivity, lifetime, and diffusion capacity can achieve multifaceted oxidative damage, significantly improving tumor eradication. Concurrently, photothermal heating and DOX release can enhance catalytic reaction rate and intracellular hydrogen peroxide levels, further amplifying polymorphic ROS generation. Both in vitro and in vivo experiments demonstrate that AP‐M@L/D induces significant intracellular oxidative stress and enhances cell‐killing efficiency by activating the apoptotic pathway. In summary, the spatiotemporally controllable polymorphic ROS can enhance antitumor efficacy and provide a guidance for ROS therapy.