Transferrin-Targeted Cascade Nanoplatform for Inhibiting Transcription Factor Nuclear Factor Erythroid 2‑Related Factor 2 and Enhancing Ferroptosis Anticancer Therapy

Ferroptosis, an iron-dependent cell death driven by the lethal levels of lipid peroxidation (LPO), becomes a promising anticancer strategy. However, the anticancer efficacy of ferroptosis is often hindered by the activation of nuclear factor erythrocyte 2-associated factor 2 (Nrf2), which is an indispensable regulator of the cellular antioxidant balance by preventing the accumulation of intracellular reactive oxygen species (ROS). Herein, we present a rational design of a Tf-targeted cascade nanoplatform TPM@AM based on mesoporous polydopamine (MPDA) co-encapsulating a ferroptosis inducer (artesunate, ART) and an Nrf2-specific inhibitor (ML385) to enhance intracellular ROS and therefore amplify ferrotherapy. Transferrin (Tf) can specifically recognize the transferrin receptor (TfR) on the surface of the cell membrane, which binds and transports iron into cells. When TPM@AM is endocytosed, the high-acid tumor microenvironment and laser irradiation trigger the collapse of MPDA to release ART and ML385. Furthermore, MPDA endows the nanoplatform with photothermal capability. The nanoplatform exhibits high efficiency for synergistic tumor suppression, representing a spatiotemporal controllable therapeutic strategy for precise synergistic cancer therapy.