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bioconjugation platforms • macromolecule hybrids • CDMO execution

Oligonucleotide–Macromolecule Conjugation

Custom conjugation of ssDNA/ssRNA, ASO, SSO, siRNA duplexes, PNA and PMO to antibodies, enzymes, carrier proteins and polymers—engineered for controlled loading (DAR‑like), site selectivity, linker behavior and analytical validation.

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Overview Modalities Platforms Strand strategy Chemistry Analytics Comparison FAQs Related Contact

Overview

Oligonucleotide–macromolecule conjugates are covalent hybrids that pair the sequence specificity of DNA/RNA with the functional complexity of biologics or polymers. The macromolecule can provide targeting (e.g., antibody), pharmacokinetic extension (e.g., albumin/Fc), catalytic activity (enzyme), or physicochemical control (polymer scaffolds).1,2

A practical design mindset is to treat the conjugate as an architecture stack: (1) oligo modality and chemistry, (2) macromolecule selection, (3) conjugation site and ratio distribution, (4) linker behavior (stable vs cleavable), and (5) analytical confirmation of the critical quality attributes (CQA).3

Supported modalities include ssDNA, ssRNA, siRNA duplexes, ASO, SSO, PNA, and PMO formats with conjugation-ready handles (thiol/amine/azide/alkyne), site-selective protein modification workflows, purification, and analytics (SEC‑HPLC/LC‑MS/UV).

Key lever Control
Ratio / DAR

Define oligo‑to‑protein distribution and remove high‑load aggregates.

Key lever Selectivity
Site selectivity

Reduce heterogeneity with cysteine, glycan, or enzymatic tagging routes.

Key lever Function
Linker behavior

Stable or cleavable (redox/pH) to match intracellular release needs.

Where these conjugates are used

Targeted RNA delivery (AOCs), PK extension (albumin/Fc), enzyme‑amplified detection, polymer-enabled multivalency/self‑assembly, and hybrid platforms for imaging and diagnostics.

ASO / SSO siRNA duplex ssDNA / ssRNA PNA / PMO AOC (antibody–oligo) Controlled loading Cleavable linkers

Supported Oligonucleotide Modalities

We conjugate single‑ and double‑stranded oligonucleotide modalities to macromolecules. Handles can be installed on the oligo (thiol/amine/azide/alkyne) and/or on the macromolecule for orthogonal, modular assembly.

Modality Strand format Common chemistries Conjugation considerations
ASO (antisense) ssDNA / ssRNA PS/PO, 2′‑OMe, 2′‑F, MOE, LNA (as needed) Handle placement away from RNase H gap/seed regions; manage protein binding from PS backbones.
SSO (splice‑switching) ss PS + 2′ chemistries, PMO (neutral) options Often steric‑block designs; neutral backbones require tailored analytics/quantitation.
siRNA dsRNA duplex Terminal PS caps, 2′‑OMe / 2′‑F patterns Strand‑selective conjugation (sense vs antisense) to preserve guide loading; duplex integrity verification.
ssDNA / ssRNA ss Labels, modified bases (program‑dependent) Used for probes/aptamer-like formats and functional scaffolds; prioritize purity and ratioing.
PNA ss (neutral) PNA backbone Neutral charge changes purification/ratioing; handle installation enables click or thiol coupling.
PMO ss (neutral) Morpholino backbone Common for steric‑block; validate conjugation without relying only on charge‑based methods.
Strand integrity & placement

For duplex RNA, define which strand carries the conjugation handle and confirm duplex integrity post‑conjugation (gel/UV melting/LC‑MS strategy as feasible). For ss modalities, define whether 3′ or 5′ attachment is function‑tolerant.

Macromolecule Conjugation Platforms

AOCTargeting
Antibody–Oligonucleotide Conjugates

Antibody–oligonucleotide conjugates (AOCs) adapt ADC-style architecture to nucleic acid payloads: defined loading distributions, site selectivity, and linker behavior to preserve binding while enabling intracellular exposure.1,2

  • Ratio control (DAR-like distributions)
  • Binding preservation and aggregation management
  • Cleavable or stable linker selection
Explore Antibody–Oligo Conjugates
EnzymeCatalysis
Enzyme–Oligonucleotide Conjugates

Catalytically active hybrids for signal amplification, activation systems, and engineered detection or proximity platforms. Orientation, linker length, and activity retention are central CQA.

  • Active-site protection during coupling
  • Flexible or rigid spacer design
  • Optional cleavable linkers for triggered release
Explore Enzyme–Oligo Conjugates
ProteinPK / targeting
Carrier Protein–Oligo Conjugates

Use carrier proteins (e.g., albumin/Fc/transferrin) to tune half-life, biodistribution, and receptor engagement. Ratio and site selectivity are used to limit heterogeneity.3

  • PK extension / reduced renal clearance
  • Receptor-mediated uptake routes
  • Controlled loading to avoid aggregation
Explore Carrier Protein Conjugates
PolymerMultivalency
Polymer–Oligo Conjugates

Polymer scaffolds (PEG and beyond) can improve solubility, tune spacing/valency, enable self-assembly, and modulate biodistribution. Architecture choices include linear, branched, and multivalent formats.4

  • PEGylation and brush architectures
  • Amphiphilic polymer–oligo self-assemblies
  • Controlled release with cleavable handles
Explore Polymer–Oligo Conjugates
OptionalSmaller targeting
Nanobody–Oligo Conjugates

Smaller targeting proteins can improve tissue penetration and reduce Fc-driven effects while retaining specificity. Consider when IgG size or Fc biology is limiting.

Explore Nanobody–Oligo Conjugates
OptionalSelf‑assembly
Optional: Peptide–Oligo (separate platform)

Peptide–oligo conjugates (including CPP-like motifs) can be used as adjacent conjugation classes or self-assembling building blocks.5

Explore Peptide–Oligo Conjugates

Strand‑Specific Conjugation Strategy

Single‑stranded formats (ASO / SSO / PNA / PMO)
  • Attachment site: 3′ vs 5′ selection based on mechanism (RNase H, steric block, binding/probe function).
  • Handle choice: thiol/amine for direct coupling; azide/alkyne for modular click assembly.
  • Backbone effects: PS increases protein binding—may change coupling kinetics and purification behavior.
Duplex formats (siRNA)
  • Strand selectivity: define whether the handle is on the sense or antisense strand to preserve guide loading.
  • Duplex integrity: verify integrity post‑conjugation (gel/UV melting/LC‑MS strategy as feasible).
  • Terminal patterns: conjugation is commonly placed at termini to minimize functional disruption.
Control objective
Maintain function while tightening heterogeneity: define attachment geometry, manage loading distributions (DAR‑like), and confirm with analytics that distinguish free oligo, free macromolecule, and conjugate species.

Conjugation Chemistry & Linker Engineering

Common coupling routes
  • Amine coupling (NHS ester) for lysine-accessible surfaces (fast, heterogeneous without control).
  • Thiol–maleimide for cysteine-directed coupling (better control; monitor linkage stability).
  • Click chemistry (SPAAC/CuAAC) using azide/alkyne handles for orthogonality and modularity.
  • Glycan-directed and enzymatic tagging strategies for improved homogeneity.
Site selectivity matters

Site-selective strategies reduce distribution breadth and improve batch reproducibility—critical when loading impacts binding, aggregation, or clearance.

Linker portfolio
Stable
Non-cleavable

Maintain intact conjugate structure for assay or surface applications.

Redox
Disulfide

Triggered in reducing intracellular environments (cytosol).

pH
Acid-labile

Cleavage in acidic endosomal/lysosomal compartments.

Enzyme
Protease-cleavable

Program-specific protease recognition sequences for gated release.

Spacer
Self-immolative

Trigger-activated spacers that unmask payload after cleavage.

Practical scoping inputs

Define oligo modality, attachment site, desired loading range, and whether macromolecule release is required. Linker class and coupling route are selected accordingly.

Quality Attributes & Analytical Validation

Typical CQAs
  • Oligo-to-macromolecule ratio distribution (DAR-like)
  • Free oligo and free protein content
  • Aggregation / high-molecular weight species
  • Integrity of the oligo and preservation of macromolecule function
  • Linker stability under storage and biological conditions
Common analytics
  • SEC‑HPLC for aggregation and distribution
  • LC‑MS for mass confirmation (as feasible by size/approach)
  • UV/Vis for ratioing (protein absorbance + oligo absorbance)
  • SDS‑PAGE for gross integrity and conjugate shifts
  • Optional: binding/activity assays (program-defined)
Documentation readiness

Conjugate programs benefit from ADC‑style CQA discipline: define handle chemistry, linker class, loading distribution, free species limits, and aggregation thresholds. COA packages can be aligned to discovery vs preclinical needs with explicit lot traceability.

Comparison of Macromolecule Conjugate Options

Platform Primary advantage Common use cases Key technical constraints
Antibody–oligo (AOC) Cell-type targeting + tissue selectivity Targeted uptake, intracellular delivery studies, precision therapeutics Loading distribution, binding preservation, aggregation/CMC complexity
Enzyme–oligo Catalytic amplification / activation Signal amplification assays, proximity systems, engineered activation Activity retention, orientation control, linker compatibility
Carrier protein–oligo PK extension and biodistribution tuning In vivo half-life extension, receptor routes (program-dependent) Heterogeneity control, clearance pathways, stability vs release tradeoffs
Polymer–oligo Solubility, spacing, multivalency, self-assembly Nanomaterials, controlled release, multivalent binding formats Architecture heterogeneity, reproducibility, characterization of distributions

Platform Taxonomy & Conjugation Architecture

Macromolecule Conjugation Platforms
  • Antibody–Oligo Conjugates (AOC) — cell‑type selective delivery
  • Enzyme–Oligo Conjugates — catalytic amplification systems
  • Carrier Protein–Oligo — PK extension & biodistribution tuning
  • Polymer–Oligo Conjugates — multivalency & physicochemical control
Adjacent Conjugation Classes
  • Peptide–Oligo Conjugates (CPP / targeting peptides)
  • Lipid–Oligo Conjugates
  • GalNAc & Receptor‑Targeted Conjugates
  • Cleavable Linker Architectures
Strategic Site Architecture

Our conjugation services are organized by macromolecule class and linker chemistry to streamline development workflows. Each platform is supported by defined coupling strategies, analytical validation, and scalable manufacturing options.

FAQ

What is an oligonucleotide–macromolecule conjugate?

A covalent construct that links a synthetic DNA/RNA (ASO, siRNA, SSO, aptamer, probe) to a biologic or polymer (antibody, enzyme, carrier protein, PEG) to tune targeting, trafficking, PK, or assay performance.

How do you control conjugation ratio (DAR / oligo-to-protein)?

We use site-selective handles (engineered cysteine, glycan remodeling, enzymatic tagging, orthogonal click reactions) plus purification and analytics (SEC-HPLC/LC-MS/UV) to quantify and tighten distributions.

Do you support cleavable linkers?

Yes. Common classes include disulfide (redox‑sensitive), acid‑labile (pH‑triggered), protease‑cleavable linkers, and optional self‑immolative spacer modules. Linker selection is matched to stability requirements and the intended release compartment.

What analytics are typical for these conjugates?

Common panels include SEC-HPLC (aggregation), IEX or RP-HPLC (purity), LC-MS (mass confirmation), UV/Vis ratioing, and gel-based methods (SDS-PAGE) where appropriate.

Can you conjugate modified oligos (PS, 2′-OMe, LNA, PMO, etc.)?

Yes. We support mixed backbone and 2′ chemistries, labels, and conjugation-ready handles (thiol, amine, azide, alkyne) on DNA/RNA and on the macromolecule.

More FAQ'sAll FAQ's

Talk to a Scientist

Share your macromolecule (antibody/enzyme/protein/polymer), intended loading range, and whether release is required. We’ll recommend site-selective chemistry, linker class, and an analytics plan.

  • Macromolecule type + available handles (lysine/cysteine/glycan/tag)
  • Desired oligo modality + chemistry (PS, 2′ chemistries, PMO, labels)
  • Stable vs cleavable linker requirement
  • Analytics expectations (SEC‑HPLC/LC‑MS/UV ratioing)
Fast scoping

For early feasibility, start with 2 builds: (1) a robust “baseline” coupling route, (2) a more site-selective route to tighten ratio distribution. Compare by aggregation + ratio + functional assay (binding/activity/knockdown as relevant).

Contact Bio‑Synthesis Custom Oligo Synthesis

Recommended Reading

Selected reviews and primary sources on antibody-, protein-, and polymer–oligonucleotide conjugation and site-selective bioconjugation.

  1. “Antibody‑Oligonucleotide Conjugates: A Twist to Antibody‑Drug Conjugates” (review). J Clin Med. 2021;10(4):838.
  2. Mullard A. “Antibody–oligonucleotide conjugates enter the clinic.” Nat Rev Drug Discov (News). 13 Dec 2021.
  3. “Synthesis of Protein‑Oligonucleotide Conjugates” (review). Biomolecules. 2022;12(10):1523.
  4. “Oligonucleotide–Polymer Conjugates: From Molecular Basics …” (review). Springer. 2020.
  5. “Chemistry of Peptide‑Oligonucleotide Conjugates: A Review.” Molecules. 2021;26(17):5420.
  6. “Site‑selective modification strategies in antibody–drug conjugates …” (review; applicable to conjugate homogeneity concepts). Chem Soc Rev. 2021.

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