Biotin-decorated celastrol-loaded ZIF-8 nanoparticles induce ferroptosis for colorectal cancer therapy

Celastrol (CEL) has garnered significant interest for its anti-tumour properties and potential for colorectal cancer (CRC) treatment. However, its clinical use is constrained by its limited bioavailability and potential toxicity. Herein, a biotin-decorated CEL nano-drug delivery system using a zeolitic imidazolate framework (ZIF-8) as a carrier was synthesized, named CEL@ZIF-8@BIO. It exhibits excellent water solubility, efficient loading of CEL, and a high release rate in acidic environments. In vitro experiments demonstrated that CEL@ZIF-8@BIO inhibited proliferation, induced cell cycle arrest in G0/G1 phase, increased ROS production and reduced mitochondrial membrane potential in CRC cells. RNA-Seq analysis indicated that the anticancer mechanism of CEL@ZIF-8@BIO may be linked to ferroptosis as indicated by a significant increase in Fe 2 +  levels, oxidative stress, lipid peroxidation, and mitochondrial dysfunction in CRC cells. Furthermore, these effects could be reversed by ferroptosis inhibitor. In vivo research revealed that CEL@ZIF-8@BIO significantly inhibited the growth of CRC tumours and reduced the toxicity associated with CEL treatment. Taken together, the CEL@ZIF-8@BIO nano-drug delivery system shows great promise for CRC therapy due to its improved efficacy and reduced toxicity.