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

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. ATO@MtrapNP construction, followed by MDM2-trap construction and mutated p53 rescuer delivering for oncotherapy is described. This strategy allows for efficient delivery of p53 mutation rescuers and thus suppresses the associated side effects. At the same time, the MDM2 trap can be constructed to efficiently inhibit MDM2 function, thereby protecting p53 from MDM2 inhibition.image

Automated summary

This study explores the inhibition of ARF expression in p53-wild-type tumors and proposes the use of ARF-mimetic MDM2-targeting reassembly peptide nanoparticles (MtrapNPs) for p53-based tumor therapy. The MtrapNPs trap MDM2 and activate p53, leading to the inhibition of p53-wild-type tumors. The study also demonstrates the therapeutic effects of using MtrapNPs to deliver arsenic trioxide for p53-mutated tumor treatment.