Engineering a cancer organoid-based platform for the early preclinical evaluation of the antitumor efficacy and safety of hydrophilic 2D metallic MoS nanosheets.

2D MoS holds significant promise for cancer therapy due to its unique physicochemical properties and biocompatibility. However, its precise effects in clinical colorectal cancer (CRC) remain poorly understood, as traditional cell-line evaluations often fail to reflect patient-specific tumor heterogeneity. To address this limitation, we developed a cancer patient-derived organoid platform for evaluating hydrophilic metallic MoS (M-MoS) nanosheets in CRC. We established paired tumor and normal colorectal organoids from patient tissues and assessed them using 3D co-culture systems along with comprehensive analytical techniques, including electron microscopy and transcriptomics. Our findings demonstrated that M-MoS nanosheets selectively suppressed CRC organoid growth without affecting normal organoids, establishing a favorable therapeutic window. Mechanistically, M-MoS nanosheets were internalized by tumor organoids and localized primarily to mitochondria, inducing reactive oxygen species production and inhibiting the PI3K-AKT signaling pathway. This triggered G2-M cell cycle arrest and apoptosis specifically in tumor organoids. To our knowledge, this is the first report of 2D MoS in a cancer patient-derived organoid platform. Our cancer organoid-based platform provides compelling evidence of the efficacy and safety 2D M-MoS for CRC treatment, while offering a robust approach for the preclinical safety and functionality assessment of advanced biomaterials, thereby accelerating their practical applications and clinical translation.