Ferrous ions doped calcium carbonate nanoparticles potentiate chemotherapy by inducing ferroptosis

Ferroptosis is a recently identified regulated cell death pathway featured in iron prompted lipid peroxidation inside cells and found to be an effective approach to suppress tumor growth. Motived by the high efficacy of ferrous ions (Fe²⁺) in initiating intracellular lipid peroxidation via the Fenton reaction, this study herein prepares a pH-responsive Fe²⁺ delivery nanocarrier by coating calcium carbonate (CaCO₃) nanoparticles with a metal-polyphenol coordination polymer composed of gallic acid (GA) and Fe²⁺. Together with simultaneous encapsulation of succinic acid conjugated cisplatin prodrugs (Pt(IV)-SA) and Fe²⁺, the yielded nanoparticles, coined as ^PGFCaCO₃, are synthesized and exhibit uniform hollow structure. After PEGylation, the resulted ^PGFCaCO₃-PEG shows increased physiological stability and pH-dependent decomposition, drug release and catalytic capability in initiating lipid peroxidation. After being endocytosed, ^PGFCaCO₃-PEG effectively promoted intracellular generation of cytotoxic reactive oxygen species including lipid peroxide, thereby exhibited superior inhibition effect towards both murine 4T1 and CT26 cancer cells over Pt(IV)-SA and ^GFCaCO₃-PEG. As a result, treatment with systemic administration of ^PGFCaCO₃-PEG effectively suppressed 4T1 tumor growth via combined Fe²⁺ initiated ferroptosis and Pt(IV)-SA mediated chemotherapy. This work highlights that intracellular delivery of Fe²⁺ is a robust approach to enhance tumor chemotherapy by inducing ferroptosis.