Synergistic Proteolysis Targeting Chimera Chemotherapy Conjugate for Potent Non-small Cell Lung Cancer Treatment

Nonsmall cell lung cancer (NSCLC) exhibits high malignancy, low survival rates, and unfavorable prognosis. As a primary chemotherapy agent for NSCLC, gemcitabine (GEM) suppresses RNA/DNA synthesis to trigger cancer cell apoptosis. Nevertheless, GEM therapy is limited by systemic toxicity and suboptimal efficacy. Combining GEM with other small-molecule kinase inhibitors frequently enhances therapeutic outcomes. Bromodomain-containing protein 4 (BRD4), a critical epigenetic regulator implicated in transcriptional control, shows strong associations with tumor progression. This study demonstrates that BRD4 degradation via the PROTAC molecule MZ1 potentiates NSCLC susceptibility to GEM. To enable codelivery, a GSH-responsive nano prodrug, BT-GEM/MZ1@NP, was strategically engineered. Compared to GEM or MZ1 monotherapy, BT-GEM/MZ1@NP demonstrated a more potent antitumor profile fostering a synergistic therapeutic through ferroptosis induction. In vivo assessment substantiated significantly enhanced tumor regression with ferroptosis promotion. These findings nominate BT-GEM/MZ1@NP as a promising clinical candidate for NSCLC therapy.