2026-10-13T19:09:51Z https://api.figshare.com/v2/oai

oai:figshare.com:article/33972898 2026-09-23T11:36:31Z category_1 category_4 category_8 category_12 category_14 category_19 category_21 category_873 category_46 category_931 category_64 portal_63 item_type_2 month_year_09_2026

Photodynamic Hijacking of APE1 Converts Tumor Defenses into Therapeutic Vulnerabilities via a Bidirectionally Gated Prodrug Hui Bian (4849063) Dandan Ma (561251) Fei Pan (255667) Zhihan Guo (14727412) Haoyang Song (16881744) Nan Yi (7495883) Myung Hwa Kim (1563310) Danhong Zhou (2113153) Haidong Li (130857) Xiaoqiang Chen (214695) Xiaojun Peng (721101) Juyoung Yoon (214704) Biophysics Biochemistry Microbiology Cell Biology Molecular Biology Pharmacology Biotechnology Chemical Sciences not elsewhere classified Immunology Information Systems not elsewhere classified Cancer potential design strategy overlooked challenge rooted minimal systemic toxicity instantaneous (∼ 100 inherent nitro group dna repair defenses dissolvable microneedle patch coordinated antioxidant buffering cooperative dual assault converts tumor defenses defense network within master regulator ape1 therapeutic vulnerabilities via ape1 inhibitor crt therapeutic vulnerabilities within minutes ape1 protein synchronous liberation steric bulk photodynamic target photodynamic hijacking photocleavable bridge localized delivery iodinated bodipy engineered bodipy endogenous quencher covalently links concerted hijacking chronically undermined beyond pioneering adaptive resistance 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, <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. 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. 2026-09-23T00:00:00Z Dataset Media 10.1021/jacs.6c13134.s002 https://figshare.com/articles/media/Photodynamic_Hijacking_of_APE1_Converts_Tumor_Defenses_into_Therapeutic_Vulnerabilities_via_a_Bidirectionally_Gated_Prodrug/33972898 CC BY-NC 4.0