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

[Display omitted] •Nanovesicle-templated nanogel PCG is built to efficiently co-load Fe3+ and DHA.•PCG-Fe/DHA achieves dual responsive intracellular release of Fe3+ and DHA.•Fe3+ and DHA in PCG cooperatively disrupt iron homeostasis to enhance ferroptosis.•PCG-Fe/DHA significantly inhibits 4T1 breast tumor growth in vivo.•Fe3+ in PCG produces higher MRI signal intensity for in vivo 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 Fe3+ 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 Fe3+ release and esterase-responsive DHA release. The concurrent delivery of Fe3+ and DHA synergistically disrupted intracellular iron homeostasis via the supplementation of exogenous Fe3+ 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 Fe3+-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 4T1 breast tumor-bearing mice achieved 76.8 %. In addition, the PCG-Fe/DHA nanogel could target tumor and produce 2.4 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.