Clustered Cobalt Nanodots Initiate Ferroptosis by Upregulating Heme Oxygenase 1 for Radiotherapy Sensitization

Abstract

High cobalt (Co) levels in tumors are associated with good clinical prognosis. An anticancer regimen that increases intratumoral Co through targeted nanomaterial delivery is proposed in this study. Bovine serum albumin and cobalt dichloride are applied to prepare cobaltous oxide nanodots using a facile biomineralization strategy. After iRGD peptide conjugation, the nanodots are loaded into dendritic mesoporous silica nanoparticles, generating a biocompatible product iCoDMSN. This nanocomposite accumulates in tumors after intravenous injection by deep tissue penetration and can be used for photoacoustic imaging. Proteomics research and molecular biology experiments reveal that iCoDMSN is a potent ferroptosis inducer in cancer cells. Mechanistically, iCoDMSNs upregulate heme oxygenase 1 (HMOX1), which increases transferrin receptors and reduces solute carrier family 40 member 1 (SLC40A1), resulting in Fe2+ accumulation and ferroptosis initiation. Furthermore, upregulated nuclear factor erythroid 2‐related factor 2 (NRF2), arising from the reduction in Kelch‐like ECH‐associated protein 1 (KEAP1) expression, is responsible for HMOX1 enhancement after iCoDMSN treatment. Owing to intensified ferroptosis, iCoDMSN acts as an efficient radiotherapy enhancer to eliminate cancer cells in vitro and in vivo. This study demonstrates a versatile Co‐based nanomaterial that primes ferroptosis by expanding the labile iron pool in cancer cells, providing a promising tumor radiotherapy sensitizer.

Intelligent nanoreactor coupling tumor microenvironment manipulation and H2O2-dependent photothermal-chemodynamic therapy for accurate treatment of primary and metastatic tumors

“…Moreover, the additional 808 nm radiation greatly improved the generation of ROS from AH@MBTF+L group owing to the more active Fenton reaction promoted by rising temperature. In addition, the intracellular •OH level was further detected by using the specific •OH-sensitive probe (BBoxiProbe®O26) [ [45] , [46] , [47] ]. As can be seen from Fig.…”

Novel methyltransferase G9a inhibitor induces ferroptosis in multiple myeloma through Nrf2/HO-1 pathway

“…FTH1 is a key iron storage protein whose light and heavy chains and Solute Carrier Family 40 Member 1 (SLC40A1) are controlled by Nrf2. and In addition, Nrf2 upregulates the expression level of heme oxygenase 1 (HO-1) [35]. The study demonstrated that inhibition of the PERK/Nrf2 pathway ameliorated resistance to G9a inhibition in leukemia cells and increased ROS and down-regulated HO-1 [36].…”

Progress and Challenges in Tumor Ferroptosis Treatment Strategies: A Comprehensive Review of Metal Complexes and Nanomedicine

“…Fenton reaction, GSH depletion, GPX4 suppression, NOXs activation, and DNA damage 4T1 cells [194] Ferroptosis PDT GOX mimicking activity, GSH depletion, and Fenton-like reaction 4T1 cells [198] iCoDMSN Co 2+ and ionizing radiation Fenton-like reaction, KEAP1 downregulation, NRF2 and HMOX1 upregulation, Fe 2+ accumulation 4T1 cells [199] BSO/ZIF8@Au@MPN@HA BSO, Au NPs, and Fe 3+ , X-ray GSH depletion, GPX4 inactivation, and Fenton reaction 4T1 cells [200] Ferroptosis Microwave therapy ADM/Fe instability of Cu + . Consequently, this has prompted researchers to explore innovative strategies to deliver Cu 2+ and subsequently convert it to Cu + within tumor cells, thereby facilitating the induction of cuproptosis.…”