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Unmodified oligonucleotides, despite their inherent specificity for target RNA or DNA sequences, suffer from poor cellular internalization due to their high molecular weight, polyanionic backbone, and hydrophilicity. Conjugation strategies have emerged as essential tools for overcoming these physicochemical barriers. By appending targeting moieties, membrane-penetrating motifs, or lipophilic carriers, oligonucleotides can bypass endosomal entrapment and exploit receptor-mediated uptake pathways.
Illustration of conjugated oligonucleotides with various functional moieties including fluorophore, peptide, small molecule, aptamer, and liposome for enhanced targeting and delivery. (BOC Sciences Original)
For example, conjugation with cell-penetrating peptides (CPPs) such as TAT or penetratin can dramatically improve intracellular localization via macropinocytosis and clathrin-independent routes. Similarly, lipid-based conjugates like cholesterol or tocopherol enhance membrane interaction and facilitate endosomal escape. Such modifications are particularly impactful in preclinical models of neurological and muscular disorders, where tissue penetration remains a critical hurdle.
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Naked oligonucleotides are highly susceptible to degradation by serum nucleases, resulting in short half-lives and reduced therapeutic index. Conjugation can stabilize oligonucleotides against enzymatic hydrolysis, either by steric hindrance or by modifying the oligo's microenvironment.
For example, PEGylation - attachment of polyethylene glycol chains—exemplifies this principle by increasing hydrodynamic radius and shielding nuclease-sensitive bonds. Moreover, conjugation with targeting ligands such as N-acetylgalactosamine (GalNAc) ensures preferential delivery to specific organs, reducing systemic exposure and minimizing off-target effects. In murine models of liver fibrosis, GalNAc-conjugated antisense oligonucleotides demonstrated tenfold increases in hepatic uptake compared to their unconjugated counterparts.
Triantennary GalNAc (N-acetylgalactosamine) clusters have become the gold standard for hepatocyte-specific delivery via asialoglycoprotein receptor (ASGPR) recognition. This receptor, abundantly expressed on liver parenchymal cells, binds GalNAc with high affinity, allowing for efficient endocytosis of the conjugated payload.
GalNAc-siRNA conjugates have shown exceptional potency in reducing hepatic gene expression with minimal dosing frequency. For instance, preclinical studies revealed >90% knockdown of target mRNA in hepatocytes using low nanomolar concentrations. BOC Sciences has extensive experience in synthesizing triantennary GalNAc conjugates with precise spatial orientation to maximize ASGPR binding affinity.
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Cholesterol-conjugated oligonucleotides benefit from improved pharmacokinetics through enhanced plasma protein binding and reduced renal clearance. This lipophilic modification facilitates passive diffusion across lipid membranes and improves access to difficult-to-transfect tissues such as the central nervous system.
PEGylation not only confers steric protection but also prolongs systemic circulation time by minimizing opsonization and uptake by the reticuloendothelial system. PEG-oligo conjugates are particularly valuable in applications where extended exposure is needed to achieve sustained gene silencing or splicing modulation.
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Targeting peptides—such as integrin-binding RGD motifs or tumor-homing ligands—provide receptor-level precision for oligonucleotide therapeutics. These peptide-oligo conjugates enable active targeting of cancer cells, immune cells, or endothelial populations depending on the ligand-receptor pair employed.
Aptamers, structured oligonucleotides selected for high-affinity binding to proteins or cell surface markers, also serve as targeting scaffolds. Aptamer–siRNA chimeras have been successfully applied to deliver gene silencers to prostate-specific membrane antigen (PSMA)-expressing cells. BOC Sciences supports the design and synthesis of peptide and aptamer conjugates using click chemistry and orthogonal ligation strategies, ensuring site-specific attachment without compromising functionality.
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Precise and controlled conjugation is essential to preserve the integrity, function, and targeting capability of therapeutic oligonucleotides. At BOC Sciences, our site-specific conjugation strategies are meticulously designed to achieve consistent, high-purity products with defined stoichiometry and spatial orientation—critical attributes for optimizing biological performance and reproducibility in preclinical studies.
(1) Chemoselective Functional Group Incorporation
Our platform enables oligonucleotides to be functionalized at predetermined sites (5'-end, 3'-end, or internal bases) with reactive groups tailored for downstream conjugation. Commonly introduced functional handles include:
This chemoselective approach ensures conjugation occurs only at designated positions, avoiding nonspecific modifications that could impair hybridization or biological activity.
(2) Conjugation Methods with High Specificity
We utilize a diverse set of conjugation chemistries depending on the physicochemical nature of both the oligonucleotide and the payload:
Our workflows accommodate diverse conjugates including sugars, peptides, lipids, fluorophores, and synthetic polymers. Each reaction is optimized to minimize side reactions, preserve the oligonucleotide's structural integrity, and achieve > 95% conjugation efficiency. Our end-to-end synthesis and conjugation services are seamlessly integrated with full analytical documentation, providing a robust foundation for downstream formulation, delivery, and preclinical validation.
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Dual-labeled and multifunctional oligonucleotides are powerful molecular tools designed to achieve advanced functionality beyond basic gene modulation. At BOC Sciences, we specialize in the rational design and synthesis of oligonucleotides equipped with multiple chemical moieties—fluorophores, affinity tags, delivery enhancers, or bioconjugation sites—each strategically positioned to retain full biological activity and improve detection, targeting, and pharmacodynamics.
(1) Dual Labeling for Quantification and Imaging
Dual-labeled oligonucleotides commonly carry a fluorophore at one terminus (e.g., 5'-FAM, Cy5) and a quencher (e.g., 3'-BHQ-1, Dabcyl) at the opposite end. These constructs are instrumental in:
BOC Sciences offers a wide range of dye-quencher pairs optimized for spectral compatibility, signal-to-noise ratio, and photostability. All dual-labeled probes are validated through spectral analysis and functional hybridization assays.
(2) Multifunctional Oligonucleotides for Modular Functionality
Our multifunctional oligos integrate multiple functional elements into a single sequence, enabling synergistic capabilities:
These constructs are particularly advantageous in complex preclinical applications where simultaneous targeting, tracking, and biological modulation are required. For example, a single oligonucleotide may be modified with a GalNAc cluster for liver targeting, a fluorophore for in vivo biodistribution imaging, and a thiol linker for conjugation to a nanocarrier.
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Comprehensive analytical characterization is a foundational pillar in the development of high-quality conjugated oligonucleotides. At BOC Sciences, we implement a rigorous and multi-dimensional quality control (QC) framework to confirm the identity, purity, structural integrity, and functionality of every synthesized oligonucleotide—particularly critical for conjugated, dual-labeled, and multifunctional constructs intended for preclinical R&D.
Comprehensive documentation accompanies every synthesis, supporting clients in regulatory submissions and preclinical data packages. Our QC standards meet or exceed current ICH guidelines for oligonucleotide-based drug development.
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BOC Sciences continues to pioneer high-performance solutions in conjugated oligonucleotide engineering. By integrating advanced conjugation chemistry, rigorous analytical control, and deep expertise in nucleic acid therapeutics, we empower our partners with precision-targeted tools for next-generation drug discovery.
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