Aptamers are short, folded oligonucleotide oligoes that through iterative process can be selected to bind molecular targets with high affinity and specificity similar to antibodies. Aptamers also have a high diagnostic potential and are readily synthesized in vitro in large libraries. We have developed a method termed APTASHAPE that exploits the capacity of oligonucleotide aptamers to recognize protein components in complex mixtures of biomolecules. We initially train a large pool (10¹⁵) of 2’F-modified, serum stable RNA fragments to recognize potentially all proteins in human plasma. In this way we enrich the pool with RNA binders (aptamers) that constitute a digital “fingerprint” of the proteins present in the body fluids. By challenging the trained pool of RNA to biofluids from individuals enables us to profile changes in the blood by monitoring the changes in the pool by NGS. We have applied APTASHAPE to analyse the proteome of urine, plasma or cerebrospinal fluid derived from a wide range of disease indications in humans and animal models suffering from various cancers, COVID-19, non-alcoholic steatohepatitis, diabetes, multiple sclerosis, Alzheimer and found that APTASHAPE analysis can, with high accuracy, diagnose disease stages and prognosis as well as treatment response. Disease-specific aptamers can subsequently be used to affinity purify proteins, which are identifiable by mass spectrometry. The APTASHAPE method require only 1 micro litre of blood, is highly cost effective, parallelizable, capable of analysis hundreds of samples on a robotic platform.