Nano-MP@PSI induces MDMX degradation and subsequent p53 as well as p73 restoration. A, WERI-Rb-1 cells were treated with Nano-MP@PSI, Nano-DPMI@PSI, Nano-PEG@PSI and Nano-MMP@PSI for 6 h at the dosage of 100 nM, and western blot was performed to analyze the expressions of MDMX, p53, p73 and p21 proteins. GAPDH was used as loading control. B, WERI-Rb-1 cells were treated with the indicated concentration of the Nano-MP@PSI for 6 h to detect the dose dependent degradation of MDMX. C, hierarchical clustering of genes differentially expressed in WERI-Rb-1 cells after exposure to 1 µM Nano-MP@PSI for 12 hours compared with mock-treated cells (n = 3). D&E, Gene set enrichment analysis (GSEA, D) and hierarchical clustering of genes (E) in p53 signaling pathway. F-J, GSEA showing the p53 downstream pathway, p73 pathway, apoptosis, cell cycle checkpoints or cell cycle mitotic signatures differentially expressed in response to Nano-MP@PSI. KEGG, Kyoto Encyclopedia of Genes and Genomes; PID, Pathway Interaction Database; Nes, normalized enrichment score. K, Dose-dependent curves of indicated samples against WERI-Rb-1 cells after 48 h incubation measured by CCK8 assay (n =4, mean ± s.d.). WERI-Rb-1 carried wildtype p53 and over-expressed MDMX. L, Apoptosis levels of Nano-MP@PSI and Nano-DPMI@PSI on WERI-Rb-1 cells were determined by Annexin V-PI staining and flow cytometric analysis.