Circulating cell-free nucleic acids in blood have recently emerged as clinically relevant and minimally invasive cancer biomarkers. However, they are challenging to detect accurately due to their low concentrations, short lengths, and high sequence homology among family members. Thus, currently available technologies to detect such biomarkers lack either sensitivity or specificity and typically rely on complex and costly procedures that are not easily amenable to incorporation into miniaturised devices. The thesis herein presents the design, engineering, and technical validation of three original platform technologies for ultrasensitive (down to single molecule) and highly sequence-specific detection of cell-free nucleic acid biomarkers (either short single-stranded microRNAs or small fragments of double-stranded DNA) from liquid biopsies. Each technology uses carefully engineered physically- or chemically-crosslinked hydrogels to either finely tune or enhance the performances of existing optical and electrical sensing platforms. Firstly, an optical-based sensing strategy for the amplification-free detection of cancer-specific microRNA is presented. It is based on oligonucleotide-templated reactions conducted within physical hydrogels, where the hydrogel matrix improved the limit of detection by four orders of magnitude (0.1 nM) compared to similar reactions carried out in solution. Next, a single-molecule electrical-based platform is developed for the detection of short (=250 bp) clinically relevant cell-free DNA based on hydrogel-filled nanopipettes. By modifying the chemical and physical properties of the hydrogel, it was possible to selectively sample only short DNA fragments and achieve size profiling in a sequence-independent manner. Finally, a skin interstitial fluid sampling platform is engineered based on hydrogel-coated microneedles, which enables cancer-specific microRNA sampling as well as on-chip and off-chip detection capabilities in ~15 min. Because of their versatility, the platforms may be developed in the future to offer multiplexing capabilities and may be integrated into portable clinical devices enabling cheaper, more accurate and timely cancer diagnosis and monitoring based on minimally-invasive liquid biopsies.