Oxidative stress-amplified nanomedicine for intensified ferroptosis-apoptosis combined tumor therapy

Ferroptosis, as an effective sensitizer for apoptosis-based cancer treatments, has been elucidated to rely on high levels of intracellular oxidative stress mediated by the accumulation of reactive oxygen species (ROS). However, ferroptosis-related oxidation effect is largely counteracted by the endogenous reductive glutathione (GSH). Here, we constructed a self-assembled metal-organic nanomedicine p53/Ce6@ZF-T, which was composed of p53 plasmid-complexed chlorin e6 (Ce6)-poly(amidoamine), Fe2+-containing mesoporous zeolitic imidazolate framework-8 and naturally derived tannic acid (TA). The highly cytotoxic ROS was continuously produced via Fe2+-mediated and TA-assisted enhanced Fenton reaction as well as Ce6-induced photosensitive reaction, and meanwhile, the intratumoral upregulated p53 expression inactivated glutathione peroxidase 4 (GPX4) to suppress lipid peroxidation (LPO) resistance, thus resulting in amplified oxidative stress and intensified ferroptosis-apoptosis therapy. The notable anticancer efficacy of p53/Ce6@ZF-T both in vitro and in vivo substantially evidenced the high feasibility of oxidative stress-amplified therapeutic modality for enhanced ferroptosis-apoptosis combined therapy, which would be a promising approach in the field of cancer treatment in the future. p53-mediated ferroptosis could remodel the sensitivity of tumors to proapoptotic therapy for intensified ferroptosis-apoptosis combined tumor therapy through an oxidative stress-amplified nanomedicine p53/Ce6@ZF-T. [Display omitted] •An oxidative stress-amplified nanomedicine (p53/Ce6@ZF-T) was designed for inducing ferroptosis-apoptosis antitumor therapy.•p53/Ce6@ZF-T combined Fenton reaction with photodynamic therapy to generate abundant highly cytotoxic ROS.•Tannic acid coating on p53/Ce6@ZF could strengthen Fenton reaction efficacy by accelerating the conversion of Fe3+ to Fe2+.•p53/Ce6@ZF-T showed an excellent expression ability of p53 protein to inactivate GPX4 activity and amplify ferroptosis.