Enhancing PARP inhibitor efficacy using reduction-responsive nanoparticles encapsulating NADP

Poly(ADP-ribose) polymerase inhibitors (PARPi) have shown success in cancer chemotherapy; however, not all tumors respond effectively to PARPi treatment, even in the presence of BRCA1/2 mutations or homologous recombination (HR) repair defects. NADP+ was recently identified as an endogenous inhibitor of ADP-ribosylation with the potential to sensitize cancer cells to PARPi, yet its lack of membrane permeability poses a significant challenge to its clinical application. In this study, we developed reduction-responsive nanoparticles (NPs) containing disulfide bonds, which can be cleaved in the reductive environment of tumor cells. These NPs encapsulate NADP+ and the commercially available PARP inhibitor olaparib. The uptake of these NPs significantly increases the intracellular concentration of NADP+, which negatively regulates DNA damage-induced PARylation and impairs DNA damage repair. The combined effects of elevated NADP+ levels and olaparib synergistically suppress tumor cell growth. Overall, our study offers a promising strategy for the clinical application of NADP+.