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Systematic Exploration of Synthesis and Function Landscapes for DNA Hydrogels Programmable biomaterials enable the control of macroscopic material properties through molecular-level design. DNA hydrogels are particularly promising among various biomolecular materials because their sequence design can be directly translated into material functionality. Rolling circle amplification (RCA) enables the fabrication of DNA hydrogels while densely encoding functional sequences such as aptamers. However, the rational design of functional RCA-based DNA hydrogels remains challenging due to the vast, interdependent space of synthesis and sequence parameters. Here we present an exploration framework using an acoustic liquid handler to systematically map both synthesis conditions and aptamer sequences. Systematic exploration across 90 synthesis conditions (270 samples) revealed the multidimensional synthesis landscape of RCA-based DNA hydrogels and identified key parameters contributing to robust gel formation. In addition, systematic sequence mapping of 96 aptamer variants (288 samples) enabled efficient discovery of color-specific aptameric mutants for functional implementation in the hydrogel. By integrating material synthesis and functional sequence exploration, this framework provides a useful strategy for accelerating the rational design of functional DNA-based materials. https://pubs.acs.org/doi/10.1021/acssynbio.6c00216