Fe(III)‐Naphthazarin Metal–Phenolic Networks for Glutathione‐Depleting Enhanced Ferroptosis–Apoptosis Combined Cancer Therapy

Abstract Nowadays, Fenton chemistry‐based chemodynamic therapy (CDT) is an emerging approach to killing tumor cells by converting endogenous H 2 O 2 into cytotoxic hydroxyl radicals (·OH). However, the elimination of ·OH by intracellular overexpressed glutathione (GSH) results in unsatisfactory antitumor efficiency. In addition, the single mode of consuming GSH and undesirable drug loading efficiency cannot guarantee the efficient cancer cells killing effect. Herein, a simple one‐step strategy for the construction of Fe 3+ ‐naphthazarin metal–phenolic networks (FNP MPNs) with ultrahigh loading capacity, followed by the modification of NH 2 ‐PEG‐NH 2 , is developed. The carrier‐free FNP MPNs can be triggered by acid and GSH, and rapidly release naphthazarin and Fe 3+ , which is further reduced to Fe 2+ that exerts Fenton catalytic activity to produce abundant ·OH. Meanwhile, the Michael addition between naphthazarin and GSH can lead to GSH depletion and thus achieve tumor microenvironment (TME)‐triggered enhanced CDT, followed by activating ferroptosis and apoptosis. In addition, the reduced Fe 2+ as a T 1 ‐weighted contrast agent endows the FNP MPNs with magnetic resonance imaging (MRI) functionality. Overall, this work is the debut of naphthazarin as ligands to fabricate functional MPNs for effectively depleting GSH, disrupting intracellular redox homeostasis, and enhancing CDT effects, which opens new perspectives on multifunctional MPNs for tumor synergistic therapy.