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Crosslinker-Modified Oligonucleotides for Bioconjugation

Custom biomolecule–oligonucleotide conjugation starts with the right crosslinker strategy. Bio-Synthesis connects oligos to antibodies, proteins, peptides, drugs, polymers, nanoparticles, lipids and surfaces using tailored crosslinker chemistry, purification and analytical QC.

AOC ODC Peptide–Oligo Nanoparticle–Oligo
Request a Custom Conjugation Quote Choose a Conjugation Strategy
Overview Planner Selector Why Crosslinkers What We Build Chemistry Capabilities Related Contact
Overview

Crosslinkers Are the Chemistry. Bioconjugates Are the Outcome.

Bio-Synthesis does more than supply modified oligonucleotides. We develop complete biomolecule–oligonucleotide conjugation strategies, from reactive handle selection and crosslinker chemistry through purification, analytical characterization and manufacturing.

Crosslinker-modified oligonucleotides are used when an oligo must be covalently connected to another biomolecule or material. Depending on the project, crosslinker chemistry can support antibody–oligonucleotide conjugates (AOCs), oligonucleotide–drug conjugates (ODCs), peptide–oligonucleotide conjugates, protein–oligonucleotide conjugates, nanoparticle–oligo conjugates, lipid conjugates, polymer conjugates and surface immobilization.

Positioning note: This page belongs under Conjugation Modifiers → Reactive Crosslinkers. Reactive handles prepare an oligo for conjugation; crosslinkers are selected to bridge the oligo to another molecule.

Conjugation Project Planner

Conjugation Project Planner

Use this project planning guide to identify the best starting point for your biomolecule–oligonucleotide conjugation project. It separates simple reactive handles, crosslinker-driven biomolecule conjugation, multifunctional modifier design and complete custom bioconjugation services.

Step 1

What is your project goal?

Add a Reactive Handle

NH₂, SH, COOH, carbonyl or click-ready oligo

Connect Two Biomolecules

Use crosslinker chemistry to join an oligo to antibody, peptide, drug, protein or material

Combine Multiple Modifications

Dual, triple and orthogonal multifunctional oligo designs

Need the Finished Conjugate

Complete conjugation, purification, QC and delivery

Step 2

Choose the best starting point

Reactive Handle Pages

Use when you only need to introduce one functional group onto the oligo.

Amino Thiol Click

Crosslinker-Modified Oligos

This page. Use when the goal is to covalently connect an oligo to another biomolecule.

Open Strategy Selector

Multifunctional Modifiers

Use when one oligo must carry multiple functions, such as DBCO + Cy5 + biotin.

View Modifiers

Custom Bioconjugation

Use when you want Bio-Synthesis to develop and deliver the finished conjugate.

View Service
Step 3

Choose your biomolecule and crosslinker strategy

Once the project goal is clear, select the biomolecule you want to conjugate below. Bio-Synthesis can then recommend compatible reactive handles, crosslinker chemistry, spacer design, purification and analytical QC.

Antibody Protein Peptide Drug Payload Nanoparticle Polymer / PEG Surface Custom Biomolecule
Conjugation Strategy Selector

Choose the Biomolecule or Material to Conjugate

Select the biomolecule or material you want to connect to an oligonucleotide. Each option shows typical reactive handles, crosslinker classes, applications and QC considerations.

Antibody Protein Peptide Drug Nanoparticle Polymer / PEG Surface
Antibody–Oligonucleotide Conjugates

AOC Strategy

Antibodies can be conjugated to DNA, RNA, aptamers or barcoded oligos using amine, thiol or click-compatible crosslinker chemistries.

Reactive Handles

NH₂, reduced cysteine, maleimide, azide, DBCO

Crosslinkers

SMCC, Sulfo-SMCC, SPDP, click pairs

Applications

Immuno-PCR, spatial biology, single-cell assays, targeted detection

Spacer

PEG or long hydrophilic spacer recommended

Purification

SEC, HPLC or project-specific

QC

UV/Vis, conjugation ratio, purity, oligo identity

Best Fit & Project Examples

  • Antibody–DNA barcodes
  • Antibody–aptamer constructs
  • Immunoassay amplification

Typical Workflow

Antibody
→
Crosslinker
→
Oligo
→
AOC ✓
Protein–Oligonucleotide Conjugates

Protein / Enzyme Strategy

Proteins and enzymes can be connected to oligos for detection, affinity, immobilization, assay development or molecular engineering workflows.

Reactive Handles

Lysine NH₂, cysteine SH, engineered tags

Crosslinkers

SMCC, BS3, DSS, SPDP, hydrazide

Applications

Enzyme–oligo, protein labeling, assay conjugates

Spacer

C6, C12, PEG or TEG

Purification

SEC, HPLC, affinity or custom

QC

Conjugation ratio, activity, mass shift, UV/Vis

Best Fit & Project Examples

  • Protein labeling
  • Enzyme conjugates
  • Affinity reagent development

Typical Workflow

Protein
→
Linker
→
DNA/RNA
→
Conjugate ✓
Peptide–Oligonucleotide Conjugates

Peptide Strategy

Peptides can be attached to siRNA, ASO, aptamers or DNA/RNA constructs to support targeting, uptake, cell penetration or receptor binding studies.

Reactive Handles

N-terminal NH₂, cysteine SH, azide, alkyne

Crosslinkers

SMCC, maleimide, NHS ester, click pairs

Applications

CPP-siRNA, peptide-ASO, targeting ligands

Spacer

PEG, TEG or cleavable linker

Purification

HPLC recommended

QC

LC-MS, HPLC, UV/Vis, purity

Best Fit & Project Examples

  • Cell-penetrating peptides
  • Receptor-targeting peptides
  • Therapeutic research conjugates

Typical Workflow

Peptide
→
SMCC / Click
→
siRNA / ASO
→
Delivery ✓
Oligonucleotide–Drug Conjugates

Drug Payload Strategy

Small molecules and drug payloads can be attached to oligos through cleavable or non-cleavable linker strategies for targeted delivery, activity studies or controlled release research.

Reactive Handles

NH₂, SH, COOH, azide, DBCO, carbonyl

Crosslinkers

Cleavable disulfide, hydrazone, click, PEG linker

Applications

ODC, payload delivery, controlled release

Spacer

PEG, acid-labile, disulfide, enzyme-cleavable

Purification

High-resolution HPLC

QC

LC-MS, HPLC, drug-to-oligo ratio, UV/Vis

Best Fit & Project Examples

  • Drug-conjugated ASOs
  • Payload–siRNA constructs
  • Cleavable linker studies

Typical Workflow

Drug
→
Cleavable Linker
→
ASO / siRNA
→
ODC ✓
Nanoparticle–Oligonucleotide Conjugates

Nanoparticle Strategy

Oligos can be attached to gold nanoparticles, magnetic beads, silica particles, quantum dots or polymeric nanoparticles for biosensors, diagnostics and nanotechnology.

Reactive Handles

SH, NH₂, COOH, biotin, azide, DBCO

Crosslinkers

Gold–thiol, EDC/NHS, streptavidin, click pairs

Applications

AuNP probes, magnetic capture, biosensors

Spacer

PEG, TEG, C12

Purification

Particle-specific cleanup

QC

DLS, UV/Vis, zeta, loading density

Best Fit & Project Examples

  • Gold nanoparticle probes
  • Magnetic bead capture
  • Nanoparticle diagnostics

Typical Workflow

NP
→
Surface Chemistry
→
Oligo
→
Probe ✓
Polymer / PEG–Oligonucleotide Conjugates

Polymer Strategy

PEG, dextran, biodegradable polymers and biomaterials can be connected to oligos for solubility, spacing, delivery, surface display or hydrogel incorporation.

Reactive Handles

NH₂, COOH, SH, azide, alkyne

Crosslinkers

EDC/NHS, maleimide, click, PEG linkers

Applications

PEGylated oligos, hydrogels, biomaterials

Spacer

PEG length project-specific

Purification

HPLC, SEC or custom

QC

HPLC, UV/Vis, mass or polymer-specific analysis

Best Fit & Project Examples

  • PEGylated oligos
  • Polymer conjugation
  • Hydrogel attachment

Typical Workflow

Polymer
→
Crosslinker
→
Oligo
→
Polymer–Oligo ✓
Surface-Immobilized Oligonucleotide Systems

Surface Strategy

Crosslinker chemistry supports oligo immobilization on glass, SPR chips, microarrays, microfluidic devices, beads, electrodes and biosensor surfaces.

Reactive Handles

NH₂, SH, COOH, biotin, azide, DBCO

Crosslinkers

EDC/NHS, maleimide, gold–thiol, streptavidin

Applications

SPR, microarrays, biosensors, beads

Spacer

C12, TEG, PEG

Purification

HPLC before immobilization

QC

Surface density, binding, hybridization access

Best Fit & Project Examples

  • Diagnostic chips
  • SPR/BLI surfaces
  • Oligo arrays and beads

Typical Workflow

Surface
→
Activation
→
Oligo
→
Immobilize ✓
Customer-Supplied Biomolecule Review

Custom Biomolecule Strategy

Custom biomolecules can often be evaluated for conjugation if their reactive groups, solubility, stability, available quantity and analytical strategy are understood.

Reactive Handles

Project-specific

Crosslinkers

Orthogonal, cleavable, photoreactive or custom

Applications

Research, diagnostics, therapeutics, proprietary workflows

Spacer

Defined by sterics and biology

Purification

Project-specific

QC

Custom analytical release

Best Fit & Project Examples

  • Customer-supplied molecules
  • Proprietary payloads
  • Novel linker workflows

Typical Workflow

Review
→
Feasibility
→
Conjugate
→
QC ✓
Why Crosslinkers Matter

Crosslinkers Control How the Biomolecules Are Connected

A reactive handle enables conjugation, but the crosslinker determines how the oligo and biomolecule are connected. Crosslinker choice influences orientation, spacer length, stability, cleavability, solubility, purification behavior and biological performance.

Reactive
Handle
Crosslinker
Chemistry
Spacer /
Linker
Biomolecule
Stable
Bioconjugate

Orientation

Controls whether coupling occurs through amines, thiols, carbonyls or orthogonal handles.

Distance

Spacer length affects steric access, hybridization, binding and surface presentation.

Stability

Non-cleavable, cleavable, disulfide, acid-labile and enzymatic linkers behave differently.

What We Routinely Conjugate

Representative Bioconjugates We Manufacture

These examples show finished biomolecule–oligonucleotide conjugates manufactured using crosslinker chemistry, reactive handles, spacer design, purification and analytical QC.

Research

assay development, uptake, imaging, affinity

Diagnostic

immuno-PCR, biosensors, arrays, detection

Therapeutic Research

AOC, ODC, CPP-siRNA, PEG-ASO

AOC

Antibody–Oligonucleotide Conjugates

AOC, antibody–DNA barcode, immuno-PCR, spatial biology and targeted detection constructs.

→

ODC

Oligonucleotide–Drug Conjugates

Drug-conjugated ASO, siRNA or aptamer constructs with cleavable or non-cleavable linker strategies.

→

PEP

Peptide–Oligo Conjugates

Cell-penetrating peptides, receptor-targeting ligands and peptide-siRNA / peptide-ASO research conjugates.

→

PRO

Protein–Oligo Conjugates

Enzymes, streptavidin, albumin, growth factors, affinity proteins and assay conjugates.

→

NP

Nanoparticle–Oligo Conjugates

Gold nanoparticles, magnetic beads, silica, quantum dots and polymeric nanoparticles.

→

PEG

Polymer & PEG Conjugates

PEGylated oligos, biodegradable polymers, hydrogels, dextran and biomaterial conjugates.

→

LIP

Lipid–Oligo Conjugates

Cholesterol, fatty acids, phospholipids and lipid-linked oligos for delivery and membrane studies.

→

SUR

Surface Immobilization

SPR, biosensors, microarrays, electrodes, microfluidic devices, beads and diagnostic chips.

→

Crosslinker Chemistry Platform

Select Crosslinker Chemistry by Reactive Group and Application

Crosslinker selection depends on available functional groups, desired stability, spacer length, water solubility, cleavability, reaction order and downstream analysis.

Representative Crosslinker Chemistry Families

Chemistry guide
Crosslinker Class Representative Crosslinkers / Handles Reactive Pair Typical Use Design Notes
Amine ↔ Thiol SMCC, Sulfo-SMCC, GMBS, SIAB, SMPB NH₂ + SH Protein-, antibody-, peptide- and oligo-conjugates Useful for connecting lysine amines to cysteine or thiol-modified oligos.
Amine ↔ Amine BS³, DSS, DSG, EGS NH₂ + NH₂ Protein crosslinking and surface coupling Can create heterogeneous products when many lysines are available.
Thiol ↔ Thiol BMH, BMOE, BM(PEG), disulfide linkers SH + SH Dual-thiol coupling and reversible linkages Thiol protection, reduction and oxidation state must be controlled.
Carbonyl / Oxime / Hydrazone Hydrazide, aminooxy, aldehyde, ketone C=O + aminooxy / hydrazide Site-specific ligation, glycan and carbonyl payload conjugation pH, buffer and linkage stability should be reviewed.
Bioorthogonal Click Azide, alkyne, DBCO, BCN, tetrazine, TCO Click pairs Orthogonal conjugation and dual-step workflows Useful when biomolecules contain many native amines or thiols.
Photoreactive Diazirine, benzophenone, aryl azide Light-activated insertion Proximity capture and protein–oligo interaction studies Light wavelength, dose and nonspecific background should be controlled.
Cleavable SPDP, Sulfo-SPDP, DTSSP, disulfide or acid-labile linkers Cleavable bridge Controlled release, ODC, pull-down, reversible capture Choose cleavage trigger based on biology and assay workflow.
Development Workflow

From Conjugation Strategy to Final Bioconjugate

Bio-Synthesis supports the full workflow from project design through synthesis, conjugation, purification and analytical QC.

01
Define Biomolecule Antibody, peptide, protein, drug, polymer, nanoparticle or surface.
02
Select Handle Choose NH₂, SH, COOH, carbonyl, azide, DBCO or other chemistry.
03
Choose Crosslinker Match spacer, solubility, cleavability and reaction compatibility.
04
Synthesize Oligo Build DNA, RNA, PNA, ASO, siRNA, aptamer or modified construct.
05
Conjugate Perform controlled coupling with project-specific conditions.
06
Purify Use HPLC, SEC, affinity or custom cleanup.
07
QC & Release Analyze identity, purity, conjugation ratio and documentation.
Why Bio-Synthesis

Beyond Crosslinkers — Complete Bioconjugation Solutions

Bio-Synthesis provides more than reactive crosslinker-modified oligonucleotides. We develop complete biomolecule conjugation strategies tailored to the chemistry, material, assay and manufacturing requirement.

Broad Biomolecule Experience

Antibodies, proteins, peptides, drugs, enzymes, lipids, polymers, nanoparticles and customer-supplied biomolecules.

Multiple Oligo Platforms

DNA, RNA, PNA, aptamers, siRNA, ASO, PMO, gapmers, branched oligos and multifunctional constructs.

Crosslinker Strategy

Heterobifunctional, homobifunctional, cleavable, photoreactive and orthogonal crosslinking strategies.

Spacer Optimization

C3, C6, C12, TEG, PEG and custom spacer designs for steric access and conjugate performance.

Analytical QC

HPLC, LC-MS, MALDI-TOF, UV-Vis, conjugation ratio, particle analysis and project-specific release testing.

Scale-Up Support

Discovery-scale research constructs through larger preclinical and development-stage conjugate supply.

Don’t See Your Biomolecule or Linker Strategy?

The examples shown on this page represent common bioconjugation projects. If your biomolecule, payload, linker chemistry or conjugation strategy is not listed, please contact Bio-Synthesis.

Our scientists routinely develop custom conjugation workflows for research, diagnostic and therapeutic applications, including novel linker chemistries, orthogonal reactions, cleavable linkers, multifunctional architectures and customer-supplied biomolecules.

Request a Custom Quote Discuss Your Project

Frequently Asked Questions

FAQ

What are crosslinker-modified oligonucleotides?
They are oligos designed with crosslinker-compatible chemistries that covalently connect DNA, RNA, PNA, aptamers or other oligos to biomolecules such as antibodies, peptides, proteins, drugs, polymers, nanoparticles or surfaces.
Is this page about crosslinker reagents or custom conjugation?
This page focuses on using crosslinker chemistry to create custom biomolecule–oligonucleotide conjugates. Crosslinkers are the enabling chemistry; the final outcome is the conjugated biomolecule or bioconjugate.
Can Bio-Synthesis make antibody–oligonucleotide conjugates?
Yes. Bio-Synthesis supports antibody–oligonucleotide conjugates and AOC-style research constructs using reactive handle selection, crosslinker chemistry, purification and analytical QC.
Can Bio-Synthesis make oligonucleotide–drug conjugates?
Yes. Oligonucleotide–drug conjugates can be evaluated using cleavable or non-cleavable linker strategies, orthogonal chemistry, payload compatibility, purification and project-specific QC.
Which crosslinker chemistry should I choose?
The best crosslinker depends on the biomolecule, available reactive groups, desired stability, spacer length, water solubility, cleavability, reaction order and QC requirements.
What QC is recommended for bioconjugates?
Common QC includes HPLC, LC-MS, MALDI-TOF, UV-Vis, conjugation efficiency, purity assessment and project-specific analysis for larger biomolecule conjugates.
What information is needed for a quote?
Provide the oligo sequence, biomolecule or payload, available reactive groups, desired linker type, scale, purification target, QC requirements and intended application.
Can customer-supplied biomolecules be conjugated?
 Yes. Customer-supplied peptides, proteins, antibodies, drugs, polymers or other biomolecules may be evaluated for custom conjugation after review of solubility, stability, reactive groups and analytical strategy.
More FAQ'sAll FAQ's
Contact & Quote Request

Need a custom biomolecule–oligonucleotide conjugate?

Send your oligo sequence, biomolecule or payload, available reactive groups, desired linker type, scale, purification target, analytical QC requirements and intended application. Bio-Synthesis can recommend a crosslinker strategy and develop a custom bioconjugation workflow.
Request a Quote Speak to a Scientist

Need help before quoting?

Email: info@biosyn.com
Phone: 800-227-0627 (US/CAN)
Phone: +001-972-420-8505 (INT)

What to Send

  • Oligo sequence and format
  • Biomolecule or payload
  • Available reactive groups
  • Desired linker or cleavability
  • Scale, purification and QC needs

What We Review

Our team evaluates reactive handle selection, crosslinker chemistry, spacer design, reaction order, purification behavior and final analytical release strategy.

Recommended Reading

Recommended Reading & Literature References

The publications below provide scientific background on bioconjugation chemistry, antibody and biomolecule conjugation, bioorthogonal chemistry, click ligation and crosslinker selection.

  1. Hermanson GT. Bioconjugate Techniques. 3rd ed. Academic Press; 2013. Foundational reference for functional groups, spacers, crosslinking reagents, labeling chemistry and conjugation workflow design.
  2. Sletten EM, Bertozzi CR. Bioorthogonal chemistry: fishing for selectivity in a sea of functionality. Angew Chem Int Ed Engl. 2009;48(38):6974–6998. doi:10.1002/anie.200900942
  3. Kolb HC, Finn MG, Sharpless KB. Click chemistry: diverse chemical function from a few good reactions. Angew Chem Int Ed Engl. 2001;40(11):2004–2021. doi:10.1002/1521-3773...
  4. Debets MF, van Berkel SS, Dommerholt J, Dirks AJ, Rutjes FPJT, van Delft FL. Bioconjugation with strained alkenes and alkynes. Acc Chem Res. 2011;44(9):805–815. doi:10.1021/ar200059z
  5. Blackman ML, Royzen M, Fox JM. Tetrazine ligation: fast bioconjugation based on inverse-electron-demand Diels–Alder reactivity. J Am Chem Soc. 2008;130(41):13518–13519. doi:10.1021/ja8053805
  6. Agarwal P, Bertozzi CR. Site-specific antibody-drug conjugates: the nexus of bioorthogonal chemistry, protein engineering, and drug development. Bioconjug Chem. 2015;26(2):176–192. doi:10.1021/bc5004982
  7. Chari RVJ, Miller ML, Widdison WC. Antibody–drug conjugates: an emerging concept in cancer therapy. Angew Chem Int Ed Engl. 2014;53(15):3796–3827. doi:10.1002/anie.201307628
  8. Prescher JA, Bertozzi CR. Chemistry in living systems. Nat Chem Biol. 2005;1(1):13–21. doi:10.1038/nchembio0605-13

Design note: References are provided for scientific background. Final crosslinker strategy should be evaluated within the context of biomolecule stability, reactive groups, oligo design, spacer length, purification method and analytical QC requirements.

Related Bio-Synthesis Technical Resources

Amino-Modified Oligonucleotides
Thiol-Modified Oligonucleotides
Carboxyl-Modified Oligonucleotides
Click-Ready Oligonucleotides
Multifunctional Oligo Modifiers
Custom Oligo Bioconjugation
Peptide-Oligo Conjugation
Antibody-Oligo Conjugation

Why Choose Bio-Synthesis

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Greetings, Researchers,

Please be advised that any information, guidelines, write-ups, and oral/video/graphic content on our website are intended solely as general guidelines.
It is the researcher's sole responsibility to conduct thorough research on the design of products intended for their experiments before submitting
their designs to Biosynthesis for production feasibility review.
Thank you for your understanding.

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