A Nucleophilicity‐Engineered DNA Ligation Blockade Nanoradiosensitizer Induces Irreversible DNA Damage to Overcome Cancer Radioresistance

Abstract During fractionated radiotherapy, DNA damage repair intensifies in tumor cells, culminating in cancer radioresistance and subsequent radiotherapy failure. Despite the recent development of nanoradiosensitizers targeting specific DNA damage repair pathways, the persistence of repair mechanisms involving multiple pathways remains inevitable. To address this challenge, a nucleophilicity‐engineered DNA ligation blockade nanoradiosensitizer (DLBN) comprising Au/CeO 2 heteronanostructure modified with trans‐acting activator of transcription peptides is reported, which targets and inhibits the DNA ligation inside cancer cell nuclei via heterointerface‐mediated dephosphorylation of DNA, a crucial step in overcoming cancer radioresistance. First, the Schottky‐type heteronanostructure of cancer cell nucleus‐targeting DLBN effectively intensifies radiation‐induced DNA damage via catalase‐mimetic activity and radiation‐triggered catalytic reactions. Notably, by leveraging Au/CeO 2 heterointerface, DLBN spontaneously dissociates H 2 O to hydroxide, a nucleophile with higher nucleophilicity, thereby exhibiting remarkable dephosphorylation capability at DNA nicks through facilitated nucleophilic attack. This enables the blockade of DNA ligation, a pivotal step in all DNA damage repair pathways, effectively interrupting the repair process. Consequently, DLBN resensitizes radioresistant cells by overcoming therapy‐induced radioresistance, leading to a substantial accumulation of unrepaired DNA damage. These findings offer insight into the dephosphorylation of DNA within nuclei, and underscore the potential of heteronanostructure‐based nanoradiosensitizer to block DNA ligation against therapy‐induced radioresistance.