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 thelethallevels of lipid peroxidation (LPO), becomes a promising anticancerstrategy. However, the anticancer efficacy of ferroptosis is oftenhindered by the activation of nuclear factor erythrocyte 2-associatedfactor 2 (Nrf2), which is an indispensable regulator of the cellularantioxidant balance by preventing the accumulation of intracellularreactive oxygen species (ROS). Herein, we present a rational designof a Tf-targeted cascade nanoplatform TPM@AM based on mesoporous polydopamine(MPDA) co-encapsulating a ferroptosis inducer (artesunate, ART) andan Nrf2-specific inhibitor (ML385) to enhance intracellular ROS andtherefore amplify ferrotherapy. Transferrin (Tf) can specificallyrecognize the transferrin receptor (TfR) on the surface of the cellmembrane, which binds and transports iron into cells. When TPM@AMis endocytosed, the high-acid tumor microenvironment and laser irradiationtrigger the collapse of MPDA to release ART and ML385. Furthermore,MPDA endows the nanoplatform with photothermal capability. The nanoplatformexhibits high efficiency for synergistic tumor suppression, representinga spatiotemporal controllable therapeutic strategy for precise synergisticcancer therapy.