A large amount of purified water is used in conventional hemodialysis (HD) for treating end-stage kidney disease (ESKD). To minimize the water demand and waste generation, the regeneration of dialysis solution is considered the most efficient control strategy. In this study, an innovative dual-layer hollow fiber (DLHF) mixed matrix membrane (MMM) incorporated with amine-functionalized mesoporous silica nanoparticles (MPS-NPs) was developed to regenerate spent dialysis solution. The fabricated DLHF-MMM configuration enabled the continuous removal of small, medium, and large weight uremic toxins (UTs) through dual mechanisms. The inner layer composed of polyethersulfone (PES) and polyethylene glycol (PEG) rejected medium-large weight UTs (i.e., MW >
500 Da) via the molecular sieving. Meanwhile, the outer layer containing amine-functionalized MPS-NPs effectively removed small weight UTs, such as urea and creatinine. The DLHF-MMM with 6 wt% of amine-functionalized MPS-NPs demonstrated the most favorable characteristics, i.e., high water permeability (298.6 ± 3.2 mL/m