The article describes the development and characterization of protein-like polymers (PLPs) that inhibit the interaction between nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associating protein 1 (Keap1). This interaction is crucial for maintaining cellular redox homeostasis and antioxidant response. The PLPs are designed to overcome the limitations of small molecule inhibitors and peptide-based strategies, which often suffer from poor cellular permeability and off-target effects. The PLPs consist of a synthetic, lipophilic polymer backbone with water-soluble Keap1-binding peptides attached to each monomer unit, forming a brush polymer architecture. These PLPs exhibit enhanced binding affinity to Keap1, maintain serum stability, and are capable of cell penetration. In vitro and in vivo studies demonstrate that PLPs selectively activate the antioxidant response element (ARE) pathway, leading to Nrf2 translocation to the nucleus and increased expression of downstream antioxidant genes. The PLPs show potential for therapeutic applications in neurodegenerative diseases (NDs) by enhancing the antioxidant response and protecting neurons and glial cells. The biocompatibility and hemocompatibility of the PLPs are also assessed, suggesting their potential for clinical translation. Overall, the PLPs represent a promising approach for targeting the Keap1/Nrf2 pathway in NDs.The article describes the development and characterization of protein-like polymers (PLPs) that inhibit the interaction between nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associating protein 1 (Keap1). This interaction is crucial for maintaining cellular redox homeostasis and antioxidant response. The PLPs are designed to overcome the limitations of small molecule inhibitors and peptide-based strategies, which often suffer from poor cellular permeability and off-target effects. The PLPs consist of a synthetic, lipophilic polymer backbone with water-soluble Keap1-binding peptides attached to each monomer unit, forming a brush polymer architecture. These PLPs exhibit enhanced binding affinity to Keap1, maintain serum stability, and are capable of cell penetration. In vitro and in vivo studies demonstrate that PLPs selectively activate the antioxidant response element (ARE) pathway, leading to Nrf2 translocation to the nucleus and increased expression of downstream antioxidant genes. The PLPs show potential for therapeutic applications in neurodegenerative diseases (NDs) by enhancing the antioxidant response and protecting neurons and glial cells. The biocompatibility and hemocompatibility of the PLPs are also assessed, suggesting their potential for clinical translation. Overall, the PLPs represent a promising approach for targeting the Keap1/Nrf2 pathway in NDs.