The study presents a novel approach to inhibit the Keap1/Nrf2 protein-protein interaction (PPI) using protein-like polymers (PLPs), which offer improved selectivity and efficacy compared to traditional small molecule or peptide-based inhibitors. PLPs are designed with Keap1-binding peptides on a hydrophobic polymer backbone, enabling them to penetrate cells and selectively activate the Nrf2 pathway. These polymers exhibit significantly higher binding affinity for Keap1 than free peptides, maintain serum stability, and demonstrate enhanced activation of the antioxidant response element (ARE) in cells, including primary cortical neurons. In vitro studies show that PLPs effectively disrupt the Keap1/Nrf2 PPI, leading to Nrf2 translocation to the nucleus and activation of ARE-dependent genes, such as HMOX1 and NQO1. PLPs also show preferential activation in astrocytes, a key cell type in neurodegenerative diseases (NDs), and demonstrate reduced hemolysis and improved biocompatibility. While PLP-10 High exhibits higher cell penetration, PLP-10 Low shows better BBB translocation, making it more suitable for in vivo studies. The results suggest that PLPs could serve as a promising therapeutic strategy for NDs and other diseases associated with oxidative stress.The study presents a novel approach to inhibit the Keap1/Nrf2 protein-protein interaction (PPI) using protein-like polymers (PLPs), which offer improved selectivity and efficacy compared to traditional small molecule or peptide-based inhibitors. PLPs are designed with Keap1-binding peptides on a hydrophobic polymer backbone, enabling them to penetrate cells and selectively activate the Nrf2 pathway. These polymers exhibit significantly higher binding affinity for Keap1 than free peptides, maintain serum stability, and demonstrate enhanced activation of the antioxidant response element (ARE) in cells, including primary cortical neurons. In vitro studies show that PLPs effectively disrupt the Keap1/Nrf2 PPI, leading to Nrf2 translocation to the nucleus and activation of ARE-dependent genes, such as HMOX1 and NQO1. PLPs also show preferential activation in astrocytes, a key cell type in neurodegenerative diseases (NDs), and demonstrate reduced hemolysis and improved biocompatibility. While PLP-10 High exhibits higher cell penetration, PLP-10 Low shows better BBB translocation, making it more suitable for in vivo studies. The results suggest that PLPs could serve as a promising therapeutic strategy for NDs and other diseases associated with oxidative stress.