Universal nucleic acid preservation in biological fluids with boron clusters

Abstract Nucleic acid preservation remains a critical bottleneck for diagnostics and therapeutics, with small molecule inhibitors such as EDTA showing limited spectrum against diverse nucleases, while protein-based alternatives requiring costly cold-chain storage. Here, we report dodecaborate cluster [B12H12]2- as a novel class of pan-nuclease inhibitor with a fundamentally different mechanism—preventing protein-nucleic acid interactions rather than targeting cofactor dependencies. [B12H12]2- inhibited all six DNases and ten RNases tested, making it the broadest spectrum nuclease inhibitor known. Remarkably, its inhibition is reversible via γ-cyclodextrin complexation. We demonstrate that [B12H12]2- preserved a physiological range of DNA for 14 days and that of RNA for 3-7 days at room temperature in human plasma and urine, achieving up to 323,972-fold better RNA retention than controls. A newly developed blood collection tube using [B12H12]2- enables whole-blood circulating cell-free RNA sequencing after 7 days of room-temperature storage, with preserved transcript integrity. Mechanistic studies suggest [B12H12]2- binds to nuclease active sites and creates electrostatic barriers that prevent substrate binding. This chemically stable, indefinitely shelf-stable inhibitor enables cold-chain-free biological sample transport, potentially transforming accessibility of nucleic acid-based diagnostics worldwide. Competing Interest Statement CUHK filed two patents based on the results of this study, with H.M.L. as the inventor.