Tumor-selective degradation of PARP-1 enabled by the codelivery of β-lapachone and PROTAC for non-small-cell lung cancer therapy

In non-small cell lung cancer (NSCLC), poly(ADP-ribose) polymerase 1 (PARP1) induces genomic instability and promotes tumor progression by impairing DNA repair pathways. Although PARP1-targeting proteolysis-targeting chimeras (PROTACs) offer a promising strategy for selective protein degradation, their clinical application remains limited by poor water solubility and insufficient tumor selectivity. Here, we report a pH-responsive magnetic nanoparticle system co-delivering β-lapachone (β-lap) and a PARP1-targeted PROTAC (PRO) for synergistic and tumor-targeting therapy. Designed with a hydrophobic self-assembled core and a magnetic coating, the nanoparticle (NP_β-lap+PRO) enables pH-responsive drug release and magnetic resonance imaging (MRI) monitoring. β-Lap is a bioactivated drug that relies on NAD(P)H:quinone oxidoreductase 1 (NQO1), which is overexpressed in NSCLC cells. It has the potential to deliver tumor-selective DNA damage and induce cell death. The NP_β-lap+PRO exploits elevated NQO1 levels in NSCLC to initiate β-lap-driven oxidative stress and DNA damage, while simultaneously enhancing PROTAC-mediated PARP1 degradation within the acidic tumor microenvironment synergistically induces apoptosis. In A549 NSCLC tumor models, this system effectively induces PARP1 degradation, blocks DNA repair, and preserves NAD(P)H pools, thereby amplifying β-lap-induced reactive oxygen species production, leading to enhanced DNA double-strand breaks and apoptosis. This study presents a biomarker-driven nanotherapeutic strategy that integrates PROTAC technology with redox-targeted combination therapy, offering a promising approach for precision treatment of NSCLC.