Abstract: Therapeutic oligonucleotides, including antisense oligonucleotides and siRNA, are modified with reactive chemical groups connected by flexible linker molecules. The modified oligonucleotides are capable of forming covalent bonds with mobile proteins, in particular with human serum albumin. While retaining biological activity, the resulting complex has enhanced cellular entry, significantly enhanced serum half-life, and reduced immune system stimulation when compared to unmodified oligonucleotides. The modified oligonucleotides overcome many problems associated with current antisense drugs. Modified oligonucleotides of the invention are administered as therapeutic agents, and hybridize to complementary sequences within targeted RNA molecules.