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

Abstract

Photodynamic therapy (PDT) for melanoma is chronically undermined by adaptive resistance, a long-overlooked challenge rooted in coordinated antioxidant buffering and DNA repair defenses. 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, APE-BDP, 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. A single green light trigger initiates near-instantaneous (∼100% within minutes) and synchronous liberation of both warheads, enabling a cooperative dual assault that potently disrupts redox homeostasis and inactivates the APE1-mediated DNA repair machinery. This concerted hijacking of the defense network within the tumor triggers multiple cell death pathways. After formulation into a dissolvable microneedle patch for localized delivery, the system effectively suppressed tumor growth in melanoma models with minimal systemic toxicity. This work establishes that the photodynamic hijacking of key regulatory proteins via intelligent molecular engineering offers a potential design strategy to subvert PDT treatment resistance.