Solid-phase synthesis of oligonucleotides is well known as an example of automated and modular molecular synthesis. This technology enables the programmable synthesis of oligonucleotides by iterative assembly of nucleosides phosphoramidites on resins. In addition to nucleosides, other small molecules can also covalently attach to oligonucleotides through solidphase phosphoramidite chemistry in high yield. These well-defined oligonucleotide-small molecule conjugates combine the functionality of small molecules and the sequence-specific target recognition of nucleic acids, expanding their potential practical uses. Fluorescence dyes/probes, hydrophobic molecules, targeting molecules and therapeutic reagents have all been conjugated with oligonucleotides for bioanalytical sensing, 2, 3 molecular assembly and drug development. In general, linkers between oligonucleotides and small molecules are non-cleavable and provide a stable connection. However, for oligonucleotide-drug conjugates in which smallmolecule drugs should be conditionally released after entering into the target cells, cleavable linkers are needed between the two entities. Cleavable linkers are molecules that join two functional moieties through a cleavable bond. Incorporation of cleavable linkers into therapeutic molecules confers advantages of site-specific and stimuli-responsive cleavage. This enables the controllable release of payload which can lower side effects and provide precision medicines. However, commonly used cleavable linkers in oligonucleotides field, photocleavage (PC) and disulfide linkers, have drawbacks for in vivo applications. For example, limited tissue penetration of ultraviolet light for cleavage of the PC linker and poor stability of disulfide linker during blood circulation. Inspired by the cathepsin B-sensitive dipeptide linkers in FDA-approved antibody-drug conjugates (ADCs), we recently reported the development of Val-Ala-02 dipeptide linker phosphoramidite for the automated synthesis of enzyme-cleavable oligonucleotides. In the Val-Ala-02 structure p-aminophenethyl alcohol, instead of self-immolative paminobenzyl alcohol, was conjugated with the dipeptide moiety. Val-Ala-02 shows excellent stability during DNA synthesis but cannot be used for the traceless release of payloads.