LASSO: versatile and selective biomolecule pulldown with combinatorial DNA-crosslinked polymers

Current methods for sequence-selective biomolecule isolation suffer from high cost, off-target effects, and limited flexibility. Here, we introduce LASSO (cross L ink- A ssisted S equence- S elective is O lation), a versatile platform using programmable polymer phase separation to capture biomolecules under native conditions. LASSO relies on combinatorial crosslinker libraries —diverse mixtures of DNA strands that collectively trigger the formation of highly swollen polymer agglomerates with near-zero background binding. We demonstrate >80% pulldown efficiency for diverse targets, including DNA, SARS-CoV-2 RNA, and human thrombin. LASSO provides 8–20x higher binding capacity (4 nmol/mg polymer) than commercial microbeads. In RNA-seq workflows, LASSO depleted ribosomal RNA with 86% efficiency while yielding up to 7x fewer off-target outliers (p<0.001) versus state-of-the-art magnetic beads ( riboPOOLs ) and RNase H ( NEBNext ) kits. Thrombin was captured via switchable aptamers with 92% efficiency, and a gentle release mechanism allowed the subsequent isolation of 72% enzymatically active proteins from the polymer. LASSO’s cost-effectiveness ($0.96/sample vs. $46–$51 for commercial kits), long-term stability (7+ years), simple usage, and modularity position it to transform diagnostics, transcriptomics, and bionanotechnology workflows.