A ROS-Responsive Dual-Targeting Drug Nanocarrier Serving as a GSI Synergist and Ferroptosis Sensitizer for T-Cell Acute Lymphoblastic Leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive hematological malignancy for which targeted therapies remain underdeveloped. Oncogenic mutations in Notch1 occur in up to 75% of T-ALL patients. Although γ-secretase inhibitors (GSIs) can block Notch1 activation, their clinical application is limited by side effects and reduced sensitivity. Here, a self-assembling, reactive oxygen species (ROS)-responsive nanotherapeutic strategy-PHD/G-NPs-co-loaded with GSI and controlled released dihydroartemisinin (DHA), and modified with a CD38 antibody is reported. The CD38 antibody specifically targets T-ALL cells, while GSI selectively inhibits Notch1, resulting in a dual-targeting approach. GSI is released first, inhibiting Notch1 activation and inducing the death of a subset of T-ALL cells. To eliminate semi-quiescent T-ALL cells that escape initial therapy by elevating ROS levels, a ROS-sensitive DHA delivery system is employed to enhance ferroptosis and boost GSI efficacy. After elucidating the mechanism of action of PHD/G-NPs in T-ALL cells, PHD/G-NPs are combined with αPD-1, which triggers an anti-tumor immune response in vivo. This dual-targeting strategy using CD38-modified PHD/G-NPs enables controlled drug release, enhances ferroptosis, mitigates GSI-induced gastrointestinal toxicity, and improves therapeutic efficacy. This nanomedical approach offers a novel strategy for targeted T-ALL treatment.