An “AND” logic gate–based supramolecular therapeutic nanoplatform for combatting drug-resistant non–small cell lung cancer

Despite targeted therapies like epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), non–small cell lung cancer (NSCLC) remains a clinical challenge due to drug resistance hampering their efficacy. Here, we designed an “AND” logic gate–based supramolecular therapeutic platform (HA-BPY-GEF-NPs) for the treatment of EGFR-TKI resistant NSCLC. This system integrates both internal and external stimuli–responsive mechanisms that need to be activated in a preset sequence, enabling it to precisely control drug release behavior for enhancing therapeutic precision. By programming the system to respond to sequential near-infrared (NIR) irradiation and enzyme (cathepsin B) inputs, the release of gefitinib is effectively confined to the tumor region. Moreover, the NIR irradiation induces reactive oxygen species production, suppressing tumor growth and inhibiting bypass signaling pathways. The designed drug delivery system offers a highly controlled and targeted therapeutic approach, effectively inhibiting tumor growth, suppressing bypass signaling pathways, and overcoming EGFR-TKI resistance, thus offering a potential solution for maximizing therapeutic benefits.