Global digital data is increasing immensely, reaching 291 zettabytes by 2030, as most human activities today are captured digitally. However, the longevity of digital storage media is limited, typically not exceeding 15 years, which poses a significant challenge for preserving valuable data. Given these challenges, synthetic deoxyribonucleic acid (DNA) emerges as a promising alternative due to its high density and longevity, making it an ideal medium for archival storage. With the development of biotechnologies over recent decades, DNA storage has transitioned from theoretical to practical. To fully utilize the advantages of DNA storage, this project will develop new algorithms and systems through cross-layer optimization by leveraging DNA storage properties, architecture design, and storage system design. The following innovations will be pursued: 1) Designing novel DNA storage algorithms for bio-domain optimization to enhance scalability; 2) Creating a novel DNA storage architecture to increase reliability and performance; and 3) Developing system management solutions for DNA storage based on traditional storage technologies. These efforts will collectively advance the scalability, reliability, and performance of DNA storage. This research aims to advance DNA storage systems, preserving human activities through centuries-long DNA storage, and deepening our understanding of the trade-offs and efficiencies necessary for scaling up DNA storage. Developing new DNA storage p