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Conjugation Chemistry

Oligonucleotide Conjugation & GalNAc Bioconjugation for Targeted RNA Therapeutics

Custom oligo conjugation and bioconjugation for DNA/RNA with a focus on GalNAc–oligo therapeutics—including siRNA–GalNAc and ASO–GalNAc conjugates—for hepatocyte targeting via the ASGPR pathway. Additional options include lipidated oligos (cholesterol, C16/C18), PEGylation, peptide tags (CPP, NLS, RGD), dyes/quencher pairs, biotin/digoxigenin, and chelators (DOTA/NOTA/DTPA).

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Overview

GalNAc-Focused Oligonucleotide Conjugation for Targeted RNA Delivery

Bio-Synthesis specializes in oligonucleotide conjugation and oligo bioconjugation with an emphasis on GalNAc–oligo therapeutics. We design and synthesize siRNA–GalNAc and ASO–GalNAc conjugates that leverage ASGPR-mediated hepatocyte uptake, enabling precise, efficient delivery to the liver.

Beyond GalNAc RNA conjugation, we offer a comprehensive portfolio: lipidated oligos (cholesterol, C16/C18, DSPE/DOPE), PEGylated oligos for PK/PD tuning, peptide conjugates (CPP, NLS, RGD), fluorescent dye/quencher probes, biotinylated oligos for capture and pull-downs, and chelator–oligo conjugates (DOTA/NOTA/DTPA) for radiometal labeling and biodistribution imaging.

Using orthogonal chemistries—thiol–maleimide, NHS–ester, and click conjugation (CuAAC/SPAAC)—we optimize linker length, payload density, and placement. Production includes dual HPLC, SAX counterion exchange, and full QC (ESI-MS, MALDI-TOF, UV). With scalable synthesis from research to preclinical supply, our conjugates are application-ready for RNA therapeutics, siRNA delivery, aptamer functionalization, and biodistribution imaging.

Conjugation Categories (GalNAc, Lipids, PEG, Peptides)

Tip: try “GalNAc”, “cholesterol”, “DOTA”, “CPP”, or “gold”.

🧪 Lipid Conjugates

Lipid-conjugated oligonucleotides enhance membrane interaction, endosomal escape, and serum half-life. Widely used in siRNA/ASO delivery; frequently paired with PEG or GalNAc to balance hydrophobicity and targeting.

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Products Usage Notes
2-Di-O-octadecyl-sn-glyceryl (DOG), DSPE, DOPE, DPPE, Ceramide/Sphingolipid, GMO, Lipid-Galactose, Lipid-Mannose Enhance membrane permeability, prolong serum half-life, enable tissue targeting Common in siRNA/ASO delivery
Cholesterol, Stearic (C18), Palmitic (C16), DHA, DSPE-PEG2000, C16-PEG Targeting + stability + pharmacokinetics Pairs well with GalNAc or PEG linkers
Technical Notes
  • Hydrophobic balance: Add PEG spacers to reduce aggregation and improve solubility.
  • Liver delivery: Cholesterol favors hepatic uptake; tailor for tissue distribution.
  • Purification: Hydrophobic lipids may require RP-HPLC and modified gradients.
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🧬 Peptide Conjugates

Peptide tags enable receptor-mediated uptake, tissue targeting, and subcellular localization. CPPs boost penetration; NLS sequences support nuclear delivery; RGD targets integrins.

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Products Usage Notes
RGD peptides; CPPs (TAT, Penetratin); NLS sequences; cleavable linkers (Val-Cit-PAB) Targeting, receptor engagement, cell/nuclear penetration Useful for targeted therapeutics and nuclear delivery
Technical Notes
  • Specificity vs. uptake: CPPs improve entry but can increase off-target uptake.
  • Cleavable linkers: Val–Cit–PAB enables intracellular release of the peptide or payload.
  • QC: MALDI-TOF/ESI-MS often used for peptide–oligo conjugate confirmation.
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💊 Small Molecules & Dyes

Fluorophores and small molecules support imaging, FRET/quencher assays, pull-downs, and hybridization workflows. Drug payloads produce hybrid therapeutic constructs when paired with cleavable linkers.

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Biotin, Digoxigenin, Dabcyl, Quenchers; FITC, Rhodamine, TAMRA; Cyanine dyes (Cy3/Cy5), NHS-fluors Detection, imaging, pull-downs, hybridization assays Widely used in qPCR, FISH, blotting
Therapeutic payloads (e.g., Doxorubicin) Hybrid drug-oligo constructs Requires payload-appropriate linkers
Technical Notes
  • Multiplexing: Use spectrally separated dyes; consider bleed-through.
  • Photostability: Choose robust dyes for long acquisitions; protect from light.
  • Payload safety: Use cleavable linkers for controlled drug release.
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🔗 Polymer / PEG Conjugates

PEG and related polymers improve solubility, reduce opsonization, and extend circulation time. PEG also provides tunable spacer length for multi-modal architectures.

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Products Usage Notes
mPEG, PEG2k, PEG10k, PEG20k, PEG-biotin Improve solubility, reduce immunogenicity, extend circulation Often used as spacers or stealth tags
PEG-lipid, PEG-GalNAc, PEG-cholesterol Dual function: targeting + solubility Modular architecture for multi-payloads
Technical Notes
  • Size matters: Longer PEG increases hydrodynamic radius but may affect affinity.
  • Shielding: PEG can reduce protein binding and immunogenicity.
  • Analytics: SEC and RP-HPLC can aid in characterizing PEGylated constructs.
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🧲 Chelators / Metal Complexes

Chelator-oligo conjugates enable radiometal labeling for PET/SPECT imaging, biodistribution, and tracking. Popular frameworks include DOTA, NOTA, and DTPA.

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Products Usage Notes
DTPA, DOTA, NOTA, TTHA, EDTA; chelator-biotin hybrids Radiolabeling and SPECT/PET imaging; biodistribution tracking Compatible with thiol/amine coupling and click chemistry
Technical Notes
  • Metal choice: Match chelator to radionuclide (e.g., NOTA for Ga, DOTA for Lu).
  • Buffer control: Use metal-free, chelator-compatible buffers to avoid competition.
  • Stability: Verify serum stability of metal–chelate–oligo complexes.
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🔬 Nanoparticle & Surface Tags

Surface-active handles allow immobilization on chips, beads, metals, or nanoparticles. Enable biosensors, microarrays, and nano-delivery systems via thiol–Au, biotin–streptavidin, or click chemistries.

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Gold nanoparticles (thiol–Au), streptavidin–biotin, azide/alkyne, DBCO, maleimide/thiol, amine/carboxy/hydrazide Biosensors, microarrays, nanoparticle delivery Surface immobilization or click chemistry routes
Technical Notes
  • Orientation: Use spacers (e.g., PEG) to reduce steric hindrance on surfaces.
  • Density: Optimize probe density for hybridization efficiency.
  • Gold–thiol: Consider exchange stability and salt conditions for Au assemblies.
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🧬 Base-Analog Conjugates

Photoreactive bases (e.g., halogenated dU/dC, psoralen, benzophenone) empower cross-linking and structure mapping. Useful in footprinting and protein–nucleic acid interaction studies.

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5-Bromo-dU, 5-Iodo-dU, Psoralen, Benzophenone Photo-reactivity for structure probing and cross-linking Pair with UV protocols; verify placement
Technical Notes
  • UV params: Select wavelength (e.g., UVA for psoralen) and dose to balance yield/specificity.
  • Site choice: Position in stable duplex regions for efficient cross-linking.
  • Readouts: Validate by denaturing gels/HPLC and MS; map with primer extension or digest-MS.
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🔚 End-Modifications

Terminal handles and blockers enable labeling, conjugation, and structural control—supporting stability, dimer prevention, capture, and downstream assembly.

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Inverted dT/dA, Spacer C3/C6/C12, dSpacer Blocking, structural manipulation, stability Prevents degradation or dimerization
5′-Thiol, 5′-Aldehyde, 5′-Maleimide, 5′-Azide, 5′-DBCO; 3′-Biotin/PEG/Cholesterol Functional attachment and terminal labeling Enables linker or payload attachment
Technical Notes
  • Orthogonality: Mix chemistries (thiol–maleimide, azide–DBCO, NHS–amine) for multi-tag builds.
  • Blocking: Inverted dT/dA prevents extension/ligation where needed.
  • Purification: Terminal hydrophobes may require RP-HPLC or PAGE.
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Delivery Format

Dual HPLC / SAX

Sodium counterion in vivo prep options for therapeutic studies.

QC Suite

ESI-MS, MALDI-TOF, UV spectrophotometry; optional SEC for conjugates.

Scales

From research to large-scale synthesis with documentation alignment.

Conjugation Chemistry & Linkers for GalNAc/siRNA/ASO

Primary Coupling Chemistries

  • NHS–Amine (amide): Fast, high-yield at pH ~7.5–8.5. Avoid primary-amine buffers (Tris) during coupling; use PBS/HEPES. Great for dyes, PEGs, ligands (e.g., NHS-PEGn-*).
  • Maleimide–Thiol (thioether): pH ~6.5–7.5, clean selectivity for cysteine/thiol handles (peptides, lipids, Au surfaces). Post-conjugation ring-opening (maleimide → maleamic acid) can improve serum stability.
  • CuAAC “click” (Azide–Alkyne): Robust, bioorthogonal; use Cu(I) with a ligand (e.g., TBTA) and a reductant. For copper-sensitive payloads, prefer SPAAC.
  • SPAAC (DBCO/BCN–Azide): Copper-free click for cells/in vivo; slightly slower and more hydrophobic—mitigate with PEG spacers.
  • IEDDA (TCO–Tetrazine): Very fast, truly bioorthogonal; excellent for late-stage tagging. Protect TCO from heat/light (isomerization risk).
  • Aldehyde–Aminooxy / Oxime; Aldehyde–Hydrazide / Hydrazone: Formed at pH ~4.5–6. Oximes are generally more stable than hydrazones; useful for cleavable or reversible linkers.
  • Disulfide exchange: Redox-cleavable in the cytosol (GSH). Useful for intracellular release of payloads/peptides.
  • Photochemical: o-Nitrobenzyl (PC), benzophenone, diazirine for light-triggered cross-linking/cleavage.

Linker / Spacer Families

  • PEG & Hydrophilic Spacers (PEG2–PEG48, HEG, Sp18): Add reach + solubility, reduce aggregation, tune PK. Typical: PEG4/PEG12/PEG24 between oligo and ligand (e.g., GalNAc, lipid, dye).
  • Alkyl Spacers (C3/C6/C12): Compact/hydrophobic; useful for membrane association (lipids). May increase nonspecific binding—balance with PEG.
  • Heterobifunctional Linkers: Directional assembly (e.g., NHS-PEGn-Maleimide, DBCO-PEGn-NHS, Azide-PEGn-NHS); connect amine-bearing oligos to thiol/azide partners cleanly.
  • Self-Immolative Cores (PAB/PABC): Payload release after trigger (enzymatic/chemical), common motif in cleavable linkers.
  • Cleavage Motifs: Disulfide (reducing cytosol), Val–Cit–PAB or GFLG (lysosomal proteases), Hydrazone/Ketal (acidic endosomes), o-Nitrobenzyl/DEACM (photo-labile).

Linker Selection Guide

Goal Recommended Handle + Linker Typical Use Notes
Hepatocyte targeting (ASGPR) Amine-oligo + NHS-PEG12-GalNAc siRNA/ASO–GalNAc PEG improves accessibility & solubility; position at 5′ end common.
Cell penetration / receptor binding Thiol-oligo + Maleimide-PEG4–12-Peptide CPP, RGD, NLS peptides Consider cleavable core if release desired (e.g., disulfide, Val–Cit–PAB).
Hydrophobic delivery boost Amine-oligo + NHS-PEG4-Cholesterol siRNA/ASO stabilization Short PEG limits hydrophobicity; monitor RP-HPLC behavior.
Copper-free bioorthogonal Azide-oligo + DBCO-PEGn-Ligand Live-cell / in vivo SPAAC avoids Cu; PEG mitigates DBCO hydrophobicity.
Fast, late-stage tagging TCO-oligo + Tetrazine-PEGn-Reporter Imaging / preclinical Extremely rapid; protect TCO from light/heat.
Radiometal labeling Amine-oligo + NHS-PEGn-DOTA/NOTA PET/SPECT, biodistribution Metal-free buffers; match chelator to radionuclide.
Pull-down / capture Amine-oligo + NHS-PEGn-Biotin Streptavidin assays PEG reduces steric hindrance; verify multivalency needs.
Endosomal release Thiol-oligo + Disulfide-PEGn-Ligand Intracellular payload release Cleaves in reductive cytosol; avoid excess reducing agents in prep.

Representative Linkers (Examples)

Linker Type Typical Use Notes Code
NHS-PEG12-Maleimide Heterobifunctional (NHS–Mal) Amine-oligo → thiol payload/peptide (directional build) PEG boosts solubility; great general-purpose spacer [NHS-PEG12-Mal]
DBCO-PEG4-NHS Heterobifunctional (SPAAC) Amine-oligo → azide ligand (copper-free click) Biocompatible; PEG helps offset DBCO hydrophobicity [DBCO-PEG4-NHS]
Azide-PEG4-NHS Installable handle Pre-install azide on oligo → later SPAAC with DBCO probe Stable staged assembly; minimal process cross-talk [Azide-PEG4-NHS]
TCO-PEG3-NHS Heterobifunctional (IEDDA) Amine-oligo → tetrazine reporter (ultra-fast click) Protect TCO from light/heat; excellent for late-stage [TCO-PEG3-NHS]
Tetrazine-PEG5-Maleimide Heterobifunctional (IEDDA + thiol) TCO-oligo capture of thiol payloads via Maleimide Bridges IEDDA and thiol chemistry cleanly [Tz-PEG5-Mal]
SMCC-type (non-PEG) NHS–Maleimide Compact, non-cleavable Amine→thiol coupling where short reach is preferred Less hydrophilic; consider RP-HPLC for purification [SMCC-type]
Disulfide-PEG8 Redox-cleavable Intracellular payload release (reductive cytosol) Avoid reducing agents during prep; validates in cell lysate [SS-PEG8]
Val–Cit–PAB (±PEGn) Protease-cleavable Lysosomal release motifs (ADC-style) Cathepsin B sensitive; confirm in relevant model [Val-Cit-PAB]
Hydrazone-PEG4 / Oxime-PEG4 pH-cleavable / reversible Endosomal release or reversible capture Oximes > hydrazones for stability; tune pH 4.5–6.0 [Hydrazone-PEG4]
PC-Spacer (o-Nitrobenzyl) Photocleavable Light-triggered release or cross-link control Choose λ to minimize off-targets; leaves trace adduct [PC-Spacer]
Maleimide-DBCO-PEG4 Bridge (thiol→azide) Two-step builds: thiol payload then SPAAC to azide Great for multi-tag constructs (payload + reporter) [Mal-DBCO-PEG4]
NHS-PEG12-GalNAc Ligand-linker Amine-oligo → GalNAc (ASGPR hepatocyte targeting) Spacer length tunes uptake; common at 5′ for siRNA/ASO [NHS-PEG12-GalNAc]

Examples shown are representative; we can align to your internal SKUs, vendor equivalents, or custom spacer lengths (PEG2–PEG48, HEG, Sp18).

Technical Notes & Pitfalls
  • Buffers: For NHS couplings, avoid Tris/amine buffers; for maleimide, avoid thiols (DTT/β-ME). Use PBS/HEPES, degas for click reactions.
  • Stoichiometry: Start ~1.2–1.5× ligand excess; verify by analytical HPLC/MS; scale equivalence based on OD/µmol.
  • Maleimide stabilization: Optional mild base (pH 8.5–9) hydrolyzes the succinimide ring to maleamic acid → reduces retro-Michael exchange in serum.
  • Hydrophilicity balance: Add PEG (4–24 units) to hydrophobic payloads (lipids, DBCO, dyes) to minimize aggregation and improve recovery.
  • Purification: Very hydrophobic conjugates often prefer RP-HPLC (wider gradients, higher organic). Ion-exchange (SAX) is useful for counterion exchange/cleanup.
  • Photo/Enzyme triggers: Validate UV dose (λ & time) or protease conditions (e.g., cathepsin B for Val–Cit) in your assay buffer.
  • Storage: Protect photo-labile groups from light; freeze aliquots to avoid repeat freeze–thaw; store TCO cold/dark.

GalNAc Spotlight: Targeted RNA Delivery

Why GalNAc?

  • ASGPR targeting: High-affinity uptake by hepatocytes for liver-directed RNA therapeutics.
  • Duplex compatibility: Works with siRNA and ASO designs (winged or fully 2′-modified backbones).
  • PK/PD control: Combine GalNAc with PEG or lipid tags to tune exposure and distribution.

Design Tips

  • Ligand format: Triantennary GalNAc is common; spacer length can modulate accessibility.
  • Placement: Terminal placement with PEG spacers can improve receptor engagement.
  • QC & Purification: RP-HPLC with full ESI-MS/MALDI confirmation; optional counterion exchange.

Need help selecting the right conjugation strategy?

We’ll recommend ligand choice, spacer length, attachment chemistry, and purification/QC to match your application.

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FAQ

When should I choose GalNAc vs lipid or peptide conjugation?

Use GalNAc for hepatocyte targeting via ASGPR (siRNA/ASO to the liver). Choose lipids (e.g., cholesterol) for broader uptake and PK tuning, or peptides (CPP, RGD, NLS) for receptor-mediated or subcellular targeting.

Do you support siRNA–GalNAc and ASO–GalNAc conjugation?

Yes. We design and synthesize siRNA–GalNAc and ASO–GalNAc constructs, optimizing spacer length, backbone (PO/PS), and purification (dual HPLC, optional SAX) with full ESI-MS/MALDI and HPLC QC.

Can GalNAc be combined with PEG or dyes?

Absolutely. PEGylation can improve solubility and adjust hydrodynamics; dyes or biotin enable tracking and pull-downs. We use orthogonal chemistries (thiol–maleimide, NHS–amine, CuAAC/SPAAC) to build multi-tag designs.

What QC and documentation do I receive?

Standard packages include ESI-MS/MALDI identity and HPLC purity; optional SEC, endotoxin, moisture, and sodium. We align reporting with your internal SKUs and provide COA with yield and method parameters.

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