Aberrant upregulation or mutations of EZH2 frequently occur in human cancers. However, the clinical benefits of EZH2 inhibitors (EZH2i) remain unsatisfactory for majority of solid tumors. Therefore, there is an urgent need to develop new strategies to expand the therapeutic benefits of EZH2i. Nanocarriers have gained increased attention due to their advantages of prolonged blood circulation, enhanced cellular uptake, and active targeting capabilities. This study aims to address the challenges of EZH2i GSK126's limited efficacy and severe adverse effects against solid tumors.A nano delivery system was developed by encapsulating GSK126 within albumin nanoparticles (GSK126 NPs).The prepared GSK126 NPs exhibited a small spherical core with an average diameter of 30.09 nm ± 1.55 nm, high drug loading capacity (16.59% ± 2.86%) and good entrapment efficiency (99.53% ± 0.208%). GSK126 NPs decreased tumor weight and volume in the B16F10 xenograft mice, while such effects were not observed in the free GSK126 group. Subsequently, histological analysis demonstrated that GSK126 NPs significantly alleviated lipid-associated liver toxicity. Additionally, GSK126 NPs can partially counteract the effects of GSK126 on MDSCs, particularly by decreasing the infiltration of M-MDSCs into tumors.Albumin-based EZH2i NPs have potent anti-cancer efficacy with tolerable adverse effects, providing promising opportunity for future clinical translation in treating solid tumors.© 2025 Yunyun Guo, Jiaqi Huang, Meng Lin, Qianqian Yin, Tengrui Zhang, Zhengyang Guo, Yuanjun Tang, Rui Cheng, Yan Wang, Yiwei Peng, Xuedi Cao, Yuqing Wang, Xianrong Qi, Yang Liu, Lixiang Xue, published by De Gruyter on behalf of the SMP.