Nanovesicle-templated nanogel: A dual-modal platform integrating intracellular iron homeostasis disruption for ferroptosis and MRI-guided tumor diagnosis

Ferroptosis is an emerging form of cell death resulting from iron-dependent massive accumulation of lipid peroxides (LPOs). Efficient iron delivery and powerful iron homeostasis disruption remain quite challenging. Herein, we designed a nanovesicle-templated nanogel PCG-Fe/DHA facilitated by the self-assembly of amphiphilic polyphosphazene and the in situ coordination of gallic acid-modified chito-oligosaccharide with Fe 3+ to co-deliver iron and dihydroartemisinin (DHA) for ferroptosis cancer therapy. PCG-Fe/DHA exhibited excellent capability of dual drug loading as well as pH-responsive Fe 3+ release and esterase-responsive DHA release. The concurrent delivery of Fe 3+ and DHA synergistically disrupted intracellular iron homeostasis via the supplementation of exogenous Fe 3+ and DHA-induced ferritin degradation, resulting in a surge in the intracellular labile iron pool to initiate the Fenton reaction. Meanwhile, the intracellular redox homeostasis was disrupted due to the decline of glutathione peroxidase 4 (GPX4) abundance by Fe 3+ -depleting glutathione (GSH). As a result, the intracellular ROS and LPOs were distinctly accumulated, which consequently enhanced ferroptosis of tumor cells. After intravenous injection of PCG-Fe/DHA, the tumor inhibition ratio in 4 T1 breast tumor-bearing mice achieved 76.8 %. In addition the nanogel could target tumor and produce 3.1 times higher magnetic resonance imaging (MRI) signal intensity than free Fe. These evidences indicated that PCG-Fe/DHA platform could provide a dual-modal strategy for ferroptosis cancer therapy and MRI-guided tumor diagnosis.