While PARP inhibitors like BMN673 (Talazoparib) have shown significant effectiveness in treating cancers with homologous recombination (HR) deficiency, their benefits are limited for HR-proficient cancers. The combination of a DNMT inhibitor (DNMTi) such as 5-azacytidine (AZA) with PARPi has been shown to enhance efficacy by inducing HR defects. However, the application of this combination is challenged by the poor bioavailability and the off-target toxicity of both drugs. Efficiently co-delivering PARPi and DNMTi via nanocarriers is complex due to their differing physicochemical properties and the challenge of achieving precise tumor targeting. Once entering biological fluids, most NPs acquire a protein corona that dictates their biological identity and behavior in the body, complicating the design of nanocarriers for predictable and enhanced tumor targeting. In our preliminary studies, we developed a small sized nanocarrier based on AZA-conjugated polymer that could efficiently load BMN673. The new formulation was more effective in suppressing tumor growth in PARPi-insensitive NSCLC tumor models compared to free drug combinations. PAZA nanocarrier demonstrated excellent tumor penetration due to a new mechanism of active targeting that involves the recruitment of fibronectin from serum proteins following systemic administration. However, the complexity of precisely controlling the protein corona, influenced by variables such as polymer structure and molecular weight, poses a significant challenge and impacts the nanocarrier's behavior in biological systems. In addition, the current PAZA carrier is non-biodegradable, which may accumulate in the body over time, raising concerns about its long-term safety. To address these issues, the first objective is to develop biodegradable bPAZA carriers and evaluate the impact of polymer structure on the protein corona composition. A detailed understanding of how NPs interact with serum proteins and the impact on biodistribution will allow for precise modulation of protein corona. The second objective focuses on conjugating cetuximab, a monoclonal antibody targeting EGFR, to a bPAZA carrier exhibiting minimal protein corona. By leveraging the benefits of cetuximab's dual role as a targeting agent and a therapeutic, the proposed work will provide a new AZA-based nanocarrier with improved specificity and efficiency for enhanced PARPi based synthetical lethal therapy.