Biochemical molecules formed by chemically or enzymatically connecting two or more molecules are known as conjugates. Therapeutic oligonucleotides can be conjugated to carrier molecules via chemical modifications or attachments to enhance the properties of oligonucleotide drugs. Conjugation enhances their stability, cellular uptake, biodistribution, and therapeutic efficacy. Conjugates can include a variety of molecules or chemical groups tailored to specific therapeutic goals.
Conjugates are selected based on the therapeutic application, target tissue, desired pharmacokinetic properties, and delivery challenges.
Antibody drug conjugates (ADCs) combine the specificity of antibodies with the efficacy or "magic bullet" of the conjugated drug. Examples are antibodies targeting cancer antigens in which the antibody is conjugated to a DNA damaging or tumor destroying drug, such as MYLOTARG or ENHERTU.
Antibody-oligonucleotide conjugates (AOCs) combine the specificity of antibodies with the gene-silencing or editing capability of oligonucleotides. Examples are antibodies targeting cancer antigens conjugated with siRNAs or ASOs.
Aptamer Conjugates allow target specific proteins or cell surface markers for therapeutic purposes. Examples are aptamers conjugated to small interfering RNA (siRNA) or antisense oligonucleotides for targeted gene silencing.
Carbohydrate conjugates exploit carbohydrate-binding receptors or lectins to target specific tissues. For example, GalNAc (N-Acetylgalactosamine) targets liver hepatocytes through the asialoglycoprotein receptor (ASGPR).
Chemical Stabilizers improve nuclease resistance and extend half-life. Examples are phosphorothioate (PS) modifications, bridged and locked nucleic acids (BNAs, LNAs), 2'-O-Methyl (2'-OMe) or 2'-O-Methoxyethyl (2'-MOE) conjugates.
Examples are cell-penetrating peptides (CPPs) facilitating the crossing of cellular membranes (for example, Tat peptides or RGD peptides).
Lipid Conjugates such as cholesteryl conjugates or palmitoyl conjugates improve cellular uptake, enhance lipophilicity, and promote delivery to specific tissues. Examples are cholesterol-enhancing uptake via lipoprotein receptors and promoting liver targeting, fatty acids like stearic acid, improving binding to serum proteins and extending circulation time, and sphingolipids used for targeted delivery to lipid raft domains in membranes.
Nanoparticle Conjugates improve delivery efficiency and targeting specificity, especially for systemic administration. Examples are lipid nanoparticles (LNPs) and gold or silica nanoparticles.
Peptide Conjugates enable receptor-mediated targeting or facilitate intracellular delivery. Examples are peptide-siRNA conjugates or peptide-oligonucleotide conjugates (POCs).
Polymer Conjugates enhance solubility, stability, and circulation time and reduce immunogenicity. Examples are immunoconjugates, polyethylene glycol (PEG) or dendritic bioconjugates, which improves water solubility and reduces renal clearance, and polysaccharides such as dextran, which can be used for stabilization and targeting.
Small Molecule Conjugates enhance stability, modulate pharmacokinetics, or enable visualization using fluorescent labels or functional groups. Examples are fluorescent Dyes, facilitating tracking and imaging, and drug molecules to create oligonucleotide-drug conjugates (ODCs) for combination therapies, or the addtion of functional groups for further modifications or functionalization.
Targeting Peptides provides tissue or cell specificity, such as peptides targeting tumor cells or specific organs for targeted cell delivery.