Understanding and controlling proton diffusion in non-conventional solvents to enable high-density DNA nano-synthesis

Advances in light‑directed DNA synthesis have renewed interest in photoacid‑generator (PAG)–based chemistries as a path toward scalable, high‑density oligonucleotide fabrication. By leveraging spatially patterned proton release to drive acid‑catalysed deprotection, these systems promise cost‑efficient production of custom sequences. However, recent progress has also highlighted key challenges that still limit performance, including uncontrolled proton diffusion that degrades spatial resolution and the difficulty of maintaining synthesis fidelity at ever‑smaller feature sizes. Together, these issues define the current frontier in developing reliable and miniaturized PAG‑enabled DNA nano-synthesis platforms.

Non‑conventional solvents provide a physically and chemically stable environment for carrying out liquid‑phase chemical reactions. Their dielectric behavior—and therefore their solvation properties—differs significantly from those of traditional solvents. Importantly, these solvation properties can be tuned by adjusting the liquid’s composition, such as by changing the salts’ concentration or adding cosolvents. This tunability can be used to control how ionic species diffuse through complex matrices, including those used in PAG–based DNA synthesis. In particular, by precisely regulating proton diffusion, the acid‑driven reactions required for nucleotide addition can be confined to the exact location and moment where they are needed. This enables high‑fidelity, high‑density DNA nano-synthesis using PAGs.

In this thesis, you will investigate the mechanisms governing proton diffusion in non‑conventional liquid media, using electrochemical experiments and potentially complementary modelling approaches