Work

Targeting histone methylation with ROS nanoparticles delivering PARPi prodrugs to amplify the stimulation of cGAS-STING for immunotherapy in ovarian cancer

Year: 2026

Type: review

Abstract: Poly(ADP-ribose) polymerase inhibitors (PARPi) has improved survival in ovarian cancer (OC), yet its efficacy is severely compromised by the restoration of homologous recombination repair and enhanced drug efflux. Here, we report a reactive oxygen species (ROS)-responsive nanoparticle (DP@NP) for the co-delivery of PARPi and DOT1L inhibitor (DOT1Li) to overcome these limitations through a dual-function mechanism. DP@NP can be triggered by ROS in cancer cells, whereupon the released PARPi induces DNA damage, while DOT1Li augments DNA damage accumulation by suppressing PARPi efflux and impairing DNA repair. This coordinated dual action promotes the accumulation of cytosolic double-stranded DNA, thereby robustly activating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. In vivo , DP@NP exhibits efficient tumor targeting and elicits pronounced antitumor activity across multiple OC models. Notably, it remodels the tumor immune microenvironment and upregulates PD-L1, thereby significantly enhancing tumor responsiveness to immune checkpoint inhibitors. This study presents a co-delivery strategy that enhances PARPi efficacy while concurrently promoting antitumor immune activation, offering a viable avenue for the treatment of OC.

Source: Materials Today Bio

DOI: 10.1016/j.mtbio.2026.103777