Selective isolation of DNA is crucial for applications in biology, bionanotechnology, clinical diagnostics and forensics. We herein report a smart methanol-responsive polymer (MeRPy) that can be programmed to bind and separate single-as well as double-stranded DNA targets. Captured targets are quickly isolated and released back into solution by denaturation (sequence-agnostic) or toehold-mediated strand displacement (sequence-selective). The latter mode allows 99.8% efficient removal of unwanted sequences and 79% recovery of highly pure target sequences. We applied MeRPy for the depletion of insulin, glucagon, and transthyretin cDNA from clinical next-generation sequencing (NGS) libraries. This step improved the data quality for low-abundance transcripts in expression profiles of pancreatic tissues. Its low cost, scalability, high stability and ease of use make MeRPy suitable for diverse applications in research and clinical laboratories, including enhancement of NGS libraries, extraction of DNA from biological samples, preparative-scale DNA isolations, and sorting of DNA-labeled non-nucleic acid targets.

3D cell and organoid cultures, which allow in vitro studies of organogenesis and carcinogenesis, rely on the mechanical support of viscoelastic matrices. However, commonly used matrix materials lack rational design and control over key cell-instructive properties. Herein, we report a class of fully synthetic hydrogels based on novel DNA libraries that self-assemble with ultra-high molecular weight polymers, forming a dynamic DNA-crosslinked matrix (DyNAtrix). DyNAtrix enables, for the first time, computationally predictable, systematic, and independent control over critical viscoelasticity parameters by merely changing DNA sequence information without affecting the compositional features of the system. This approach enables: (1) thermodynamic and kinetic control over network formation; (2) adjustable heat-activation for the homogeneous embedding of mammalian cells; and (3) dynamic tuning of stress relaxation times over three orders of magnitude, recapitulating the mechanical characteristics of living tissues. DyNAtrix is self-healing, printable, exhibits high stability, cyto- and hemocompatibility, and controllable degradation. DyNAtrix-based 3D cultures of human mesenchymal stromal cells, pluripotent stem cells, canine kidney cysts, and human placental organoids exhibit high viability (on par or superior to reference matrices), proliferation, and morphogenesis over several days to weeks. DyNAtrix thus represents a programmable and versatile precision matrix, paving the way for advanced approaches to biomechanics, biophysics, and tissue engineering.

Selective isolation of DNA is crucial for applications in biology, bionanotechnology, clinical diagnostics and forensics. We herein report a smart methanol-responsive polymer (MeRPy) that can be programmed to bind and separate single-as well as double-stranded DNA targets. Captured targets are quickly isolated and released back into solution by denaturation (sequence-agnostic) or toehold-mediated strand displacement (sequence-selective). The latter mode allows 99.8% efficient removal of unwanted sequences and 79% recovery of highly pure target sequences. We applied MeRPy for depletion of insulin cDNA from clinical next-generation sequencing (NGS) libraries. This step improved data quality for low-abundance transcripts in expression profiles of pancreatic tissues. Its low cost, scalability, high stability and ease of use make MeRPy suitable for diverse applications in research and clinical laboratories, including enhancement of NGS libraries, extraction of DNA from biological samples, preparative-scale DNA isolations, and sorting of DNA-labeled non-nucleic acid targets.