A ROS-Responsive Dimeric Prodrug Nanoassembly for Amplified Epigenetic Therapy of Lymphoma

The clinical utility of histone deacetylase inhibitors (HDACi) like vorinostat (SAHA) in lymphoma is constrained by poor pharmacokinetics and off-target toxicity. To address this, we developed a reactive oxygen species (ROS)-responsive homodimeric SAHA prodrug (SAHA-tk-SAHA) linked via a thioketal bridge, which self-assembled into PEGylated nanoparticles (tk-diSAHA NP). These monodisperse nanoparticles (119.3 ± 4.0 nm) demonstrated excellent stability and ROS-triggered drug release (68.18 ± 2.25% with 10 mM H₂O₂ vs 6.24% in PBS over 48 h). In vitro, tk-diSAHA NP induced G₀/G₁ cell cycle arrest and apoptosis in lymphoma cells. In A20 lymphoma-bearing mice, intravenous tk-diSAHA NP achieved superior tumor growth inhibition (615.18 ± 147.88 mm³) compared to oral SAHA (1134.78 ± 311.31 mm³, p < 0.05), with enhanced histone H3 acetylation in tumors and no appreciable systemic toxicity. This ROS-activatable nanoprodrug platform presents a promising strategy to enhance the efficacy and safety of HDACi-based epigenetic therapy for lymphoma.