High-Yield Prebiotic Polymerization of 2′,3′-Cyclic Nucleotides under Wet–Dry Cycling

The spontaneous formation of RNA polymers is a fundamental yet challenging step for the origin of life. Here we show that 2',3'-cyclic nucleotides of all four nucleobases efficiently polymerize without external activators when subjected to wet-dry cycling at room temperature in a mild alkaline pH range. We found conditions where oligomerization yields (Y) are enhanced by wet-dry cycling, reaching Y ≈ 70% for guanosine and Y ≥ 20% for other nucleobases. Microscopy monitoring during the drying process indicates that guanosine's higher reactivity stems from its self-assembly propensity at pH ≤ 10. At pH 11, guanosine ordering is disfavored, leading to a nearly stoichiometrically balanced polymerization of the four nucleotides with Y = 36%. Only water is added at each cycle, mimicking humid nights and dry days on early Earth. This leads to a broad distribution of A, U, G, and C mixed sequence oligomers, up to 6% of 4-mer and 0.1% of 10-mer, paving the way for RNA replication and evolution through subsequent templated ligation under the same pH. The combination of simple boundary conditions and a pathway toward RNA evolution makes this process a compelling model for the prebiotic origin of RNA on early Earth.