Ferrous Fumarate-Encapsulated Nanoformulation Triggering a Domino Effect for Enhanced Ferroptosis Therapy

Fenton-induced ferroptosis has emerged as a promising therapeutic strategy for malignant tumors. However, the therapeutic efficacy of ferroptosis is limited by factors such as suboptimal Fenton efficiency, intracellular antioxidant systems, and insufficient drug accumulation. Here, we report a domino effect triggered by a homologous cancer cell membrane-camouflaged nanoformulation: disrupting intracellular redox homeostasis, inducing enhanced oxidative stress and leading to specific ferroptosis. This strategy involves using pure red-emission upconversion nanoparticles (NaErF₄:4%Tm@NaYF₄, U NPs), a ferroptosis inducer (ferrous fumarate, an iron-deficiency anemia therapeutic reagent), and glucose oxidase (GOx). The nanoformulation, U@mSiO₂/ferrous fumarate/GOx@lecithin/cell membrane (USFGM), enables efficient in vivo deep tissue upconversion luminescence (UCL) imaging by pure red-emission. Lecithin-modified cancer cell membranes are characterized by homologous target "homing" and acid-responsive release. Exogenous GOx depletes intratumoral glucose and generates H⁺/H₂O₂, which disrupts the nutrient supply and promotes efficient generation of reactive oxygen species (ROS). Subsequently, Fe²⁺/fumaric acids (FAs) are acid-responsively released from ferrous fumarate, which synchronously triggers and exacerbates the process of ferroptosis through mechanisms such as lipid ROS generation and glutathione (GSH) depletion. Here, we report for the first time that FA depletes GSH and leads to inactivation of GSH-dependent peroxidase 4 (GPX4). This concept is also confirmed in tumor-bearing mice of salivary adenoid cystic carcinoma (SACC). In summary, this work identifies a systemic, low-toxicity, and highly efficient cancer inhibitory nanoformulation from existing clinical drugs, which provides a promising direction for exploring therapeutic strategies for human malignant tumors.