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

Abstract Radiosensitizers hold great promise for enhanced cancer radiotherapeutics. However, apoptosis evasion of cancerous cells usually limits the efficiency of radiosensitive strategies. Herein, an in situ self‐assembled supramolecular antagonist is developed to reinforce the treatment outcome of radiotherapy by inhibiting tumor apoptosis evasion. The supramolecular antagonist is composed of self‐assembled peptide functionalized with apoptosis‐inducing peptide SmacN7 and alkaline phosphatase (ALP)‐responsive group. Upon reaching the tumor site, the supramolecular antagonist can in situ form membrane‐localized nanofibers triggered by ALP overexpressing in tumor cells, leading to enhanced cellular internalization. As a result, the cell‐permeable supramolecular antagonist effectively binds to the inhibitor of apoptosis proteins (IAPs) and eliminates their inhibitory effect on caspase activity, thereby remarkably blocking the apoptosis evasion of tumor cells and boosting the therapeutic efficacy of radiotherapy. Furthermore, in vivo studies confirm that treatment with in situ self‐assembled supramolecular antagonists can enhance radiation‐induced tumor destruction without perceptible systemic toxicity. This study offers a novel strategy of tumor apoptosis evasion inhibition to potentiate radiotherapy, which may be instructive to the development of advanced cancer therapies.