MDM2‐Targeting Reassembly Peptide (TRAP) Nanoparticles for p53‐Based Cancer Therapy

Abstract Gene mutations and functional inhibition are the major obstacles for p53‐mediated oncotherapy. For p53‐wild‐type tumors, the underlying mechanisms of functional inhibition of p53 during oncogenesis are unknown. The results reveal that the expression of the MDM2 inhibitor ARF is inhibited in p53‐wild‐type tumors, indicating that the restoration of ARF could be a potential oncotherapy strategy for p53‐wild‐type tumors. Therefore, ARF‐mimetic MDM2‐targeting reassembly peptide nanoparticles (MtrapNPs) for p53‐based tumor therapy is developed. The results elucidated that the MtrapNPs respond to and form a nanofiber structure with MDM2. By trapping MDM2, the MtrapNPs stabilize and activate p53 for the inhibition of p53‐wild‐type tumors. In most cases, reactivated mutant p53 is inhibited and degraded by MDM2. In the present study, MtrapNPs are used to load and deliver arsenic trioxide, a p53 mutation rescuer, for p53‐mutated tumor treatment in both orthotopic and metastatic models, and they exhibit significant therapeutic effects. Therefore, the study provides evidence supporting a link between decreased ARF expression and tumor development in patients with p53‐wild‐type tumors. Thus, the MDM2‐trap strategy, which addresses both the inhibition and mutations of p53, is an efficient strategy for the treatment of p53‐mutated tumors.