Synergistic albumin nanoplatform with pseudo-parabola-tuned chemotherapy and PROTAC-induced BRD4 degradation for amplified cancer therapy

The therapeutic potential of DNA-damaging agents like the topoisomerase I inhibitor exatecan (Exa) is frequently hindered by two major limitations: unfavorable physicochemical properties and intrinsic cellular defense mechanisms such as DNA repair pathways. To address these challenges, four albumin-binding prodrugs (C8-Exa, C12-Exa, C14-Exa, and C16-Exa) were developed by conjugating Exa with saturated fatty acids of varying chain lengths as albumin-binding motifs, integrated with a valine-citrulline dipeptide linker for cathepsin B (CTSB)-responsive activation, enabling their formulation into albumin nanoparticles (ANPs). Structure–activity relationship studies revealed a pseudo-parabolic trend in both albumin affinity and CTSB responsiveness as a function of fatty-acid chains, with C14-Exa ANPs achieving the optimal balance. C14-Exa ANPs exhibited superior albumin affinity, drug release kinetics, colloidal stability, and pharmacokinetics, achieving stronger tumor regression. To further amplify DNA-damaging therapeutics, hybrid ANPs (C14-ARV ANPs) were engineered by co-assembling C14-Exa with the BRD4-targeting PROTAC ARV-825, which acts through an “empty extinguisher” mechanism to disable DNA repair defenses. This dual-functional nanoplatform synergistically suppresses tumor growth by combining a structure-optimized Exa prodrug that ensures efficient DNA damage induction with ARV-825-mediated BRD4 degradation, which disrupts DNA damage repair progression and promotes apoptosis. This work establishes a rational nanoplatform design to enhance DNA damage-amplified cancer therapy. Hybrid albumin nanoparticles co-deliver optimized fatty acid-modified exatecan prodrug and ARV-825, where exatecan induces DNA damage and ARV-825-mediated BRD4 degradation blocks repair, synergistically enhancing antitumor efficacy with improved safety.