In Situ Self-Assembly Supramolecular Antagonist Reinforces Radiotherapy by Inhibiting Tumor Apoptosis Evasion

摘要

Radiosensitizers hold great promise for enhanced cancer radiotherapeutics.However, apoptosis evasion of cancerous cells usually limits the efficiency ofradiosensitive strategies. Herein, an in situ self-assembled supramolecularantagonist is developed to reinforce the treatment outcome of radiotherapy byinhibiting tumor apoptosis evasion. The supramolecular antagonist iscomposed of self-assembled peptide functionalized with apoptosis-inducingpeptide SmacN7 and alkaline phosphatase (ALP)-responsive group. Uponreaching the tumor site, the supramolecular antagonist can in situ formmembrane-localized nanofibers triggered by ALP overexpressing in tumorcells, leading to enhanced cellular internalization. As a result, thecell-permeable supramolecular antagonist effectively binds to the inhibitor ofapoptosis proteins (IAPs) and eliminates their inhibitory effect on caspaseactivity, thereby remarkably blocking the apoptosis evasion of tumor cells andboosting the therapeutic efficacy of radiotherapy. Furthermore, in vivo studiesconfirm that treatment with in situ self-assembled supramolecularantagonists can enhance radiation-induced tumor destruction withoutperceptible systemic toxicity. This study offers a novel strategy of tumorapoptosis evasion inhibition to potentiate radiotherapy, which may beinstructive to the development of advanced cancer therapies.