Therapeutic potentials of FexMoyS-PEG nanoparticles in colorectal cancer: a multimodal approach via ROS-ferroptosis-glycolysis regulation

Abstract Improving cancer therapy by targeting the adverse tumor microenvironment (TME) rather than the cancer cells presents a novel and potentially effective strategy. In this study, we introduced Fe x Mo y S nanoparticles (NPs), which act as sequential bioreactors to manipulate the TME. Fe x Mo y S NPs were synthesized using thermal decomposition and modified with polyethylene glycol (PEG). Their morphology, chemical composition, and photothermal properties were characterized. The capability to produce ROS and deplete GSH was evaluated. Effects on CRC cells, including cell viability, apoptosis, and glycolysis, were tested through various in vitro assays. I n vivo efficacy was determined using CRC-bearing mouse models and patient-derived xenograft (PDX) models. The impact on the MAPK signaling pathway and tumor metabolism was also examined. The Fe x Mo y S NPs showed efficient catalytic activity, leading to increased ROS production and GSH depletion, inducing ferroptosis, and suppressing glycolysis in CRC cells. In vivo, the NPs significantly inhibited tumor growth, particularly when combined with NIR light therapy, indicating a synergistic effect of photothermal therapy and chemodynamic therapy. Biosafety assessments revealed no significant toxicity in treated mice. RNA sequencing suggested that the NPs impact metabolism and potentially immune processes within CRC cells. Fe x Mo y S NPs present a promising multifaceted approach for CRC treatment, effectively targeting tumor cells while maintaining biosafety. The nanoparticles exhibit potential for clinical translation, offering a new avenue for cancer therapy.