Carrier-free nanoprodrug for p53-mutated tumor therapy via concurrent delivery of zinc-manganese dual ions and ROS

Human cancers typically express a high level of tumor-promoting mutant p53 protein (Mutp53) with a minimal level of tumor-suppressing wild-type p53 protein (WTp53). In this regard, inducing Mutp53 degradation while activating WTp53 is a viable strategy for precise anti-tumor therapy. Herein, a new carrier-free nanoprodrug (i.e., Mn-ZnO2 nanoparticles) was developed for concurrent delivery of dual Zn-Mn ions and reactive oxygen species (ROS) within tumor to regulate the p53 protein for high anti-tumor efficacy. In response to the mild tumor acidic environment, the released Zn2+ and H2O2 from Mn-ZnO2 NPs induced ubiquitination-mediated proteasomal degradation of Mutp53, while the liberative Mn2+ and increased ROS level activated the ATM-p53-Bax pathway to elevate WTp53 level. Both in vitro and in vivo results demonstrated that pH-responsive decomposition of Mn-ZnO2 NPs could effectively elevate the intracellular dual Zn-Mn ions and ROS level and subsequently generate the cytotoxic hydroxyl radical (•OH) through the Fenton-like reaction. With the integration of multiple functions (i.e., carrier-free ion and ROS delivery, tumor accumulation, p53 protein modulation, toxic •OH generation, and pH-activated MRI contrast) in a single nanosystem, Mn-ZnO2 NPs demonstrate its superiority as a promising nanotherapeutics for p53-mutated tumor therapy.