Photodynamic Hijacking of APE1 Converts Tumor Defenses into Therapeutic Vulnerabilities via a Bidirectionally Gated Prodrug

Herein, we propose a novel photodynamic sabotage approach that converts tumor defenses into therapeutic vulnerabilities by hijacking one important defense hub, the APE1 protein. This was achieved through creating a bidirectionally gated theranostic prodrug, <b>APE-BDP</b>, which covalently links an iodine-engineered BODIPY to the APE1 inhibitor CRT through a photocleavable bridge.

Beyond pioneering the master regulator APE1, as a photodynamic target, the molecular design strategically repurposes the inherent nitro group on CRT as an endogenous quencher that establishes a photoinduced electron transfer process to silence the iodinated BODIPY. Meanwhile, the steric bulk of the conjugate concurrently physically blocks the CRT–APE1 engagement. This bidirectional gating mechanism ensures reciprocal deactivation in the dark.