Engineering a cancer organoid-based platform for the early preclinical evaluation of the antitumor efficacy and safety of hydrophilic 2D metallic MoS2 nanosheets

2D MoS₂ 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 MoS₂ (M-MoS₂) 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-MoS₂ nanosheets selectively suppressed CRC Organoid growth without affecting normal organoids, establishing a favorable therapeutic window. Mechanistically, M-MoS₂ 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 MoS₂ in a Cancer patient-derived Organoid platform. Our Cancer organoid-based platform provides compelling evidence of the efficacy and safety 2D M-MoS₂ 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.