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Oligonucleotide Delivery & Targeting Modifications

Delivery ligands, conjugates and targeting chemistries for ASO, siRNA, aptamer and advanced oligonucleotide programs.

GalNAc • Mannose • Folate • B12 Cholesterol • Lipids • Fatty Acids CPP • Peptide • Aptamer • Antibody PEG • Albumin Binding • Cleavable Linkers HPLC/UPLC • LC-MS • CoA
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Overview

Design Oligonucleotides Around the Delivery Problem

Effective oligonucleotide therapeutics require more than sequence design. Delivery and targeting modifications can improve cellular uptake, tissue selectivity, pharmacokinetics, biodistribution and intracellular trafficking while helping overcome rapid clearance, limited uptake and endosomal trapping.

Bio-Synthesis supports custom oligonucleotide delivery and targeting modification programs for antisense oligonucleotides (ASO), siRNA, RNA therapeutics, aptamers and advanced oligonucleotide constructs. Available capabilities include GalNAc conjugation, cholesterol and lipid modifications, cell-penetrating peptides (CPPs), PEGylation, aptamer and antibody conjugates, cleavable linkers, multivalent architectures and custom oligonucleotide bioconjugation.

Our team supports the complete workflow from modification selection and conjugate design through custom synthesis, purification, LC-MS characterization, analytical QC, scale-up manufacturing and project-specific documentation for research and therapeutic development programs.

Delivery Strategy Selection

Start with the biological problem first, then select the chemistry, ligand, linker and analytical path.

Target Specific Tissues

Use receptor-targeting ligands when the main goal is tissue or cell selectivity.

GalNAc Aptamer Antibody Folate

Improve Cellular Uptake

Use hydrophobic anchors or cell-penetrating motifs when internalization limits activity.

Cholesterol Lipids CPP DAG

Extend Exposure

Use PK and solubility modifiers when circulation time or biodistribution requires tuning.

PEG Albumin Binder Tocopherol Squalene

Engineer Release

Use cleavable linkers or multivalent scaffolds when release timing or valency is important.

Disulfide Hydrazone Doubler Dendrimer

Delivery & Targeting Technology Portfolio

Tabbed Delivery Modification Platform

The tab layout keeps the full delivery offer visible without turning the page into a long chemistry catalog. Use the tabs to explore targeting ligands, uptake enhancers, PK modifiers and advanced conjugate systems.

Explore delivery and targeting modification technologies by category →

Targeting Ligands at a Glance

Best forCell / tissue selectivity
Common useASO • siRNA • Aptamer
Design focusReceptor + linker
QC focusConjugate identity
Targeting Ligand Primary Target / Function Common Oligo Fit Design & Manufacturing Note Code
GalNAc Tri-Antenna ASGPR-mediated hepatocyte targeting siRNA, ASO, gapmer 3′ placement and defined linker geometry are commonly evaluated early. [GalNAc3]
GalNAc Tetra-Antenna Higher-valency liver targeting siRNA, ASO Useful when avidity and ligand display require optimization. [GalNAc4]
Mannose Mannose receptor targeting ASO, siRNA, aptamer conjugates Often considered for macrophage or dendritic-cell focused research. [Man]
Folate Folate receptor-positive cells ASO, siRNA, aptamer or drug-oligo systems Evaluate receptor expression, linker placement and payload release. [FA]
Vitamin B12 Cobalamin receptor-mediated uptake Exploratory oligonucleotide delivery Useful for receptor-mediated uptake studies and conjugate feasibility. [B12]
Aptamer Conjugates Programmable receptor targeting Aptamer-siRNA, aptamer-ASO, aptamer-drug systems Requires structure-preserving conjugation and functional binding review. [Apt-Oligo]
Antibody-Oligo Conjugates Cell-specific targeting through antibody recognition ASO, siRNA, payload and detection systems May use maleimide-thiol, click chemistry or site-selective conjugation strategies. [AOC]
RGD / iRGD Peptides Integrin-binding tumor homing and penetration siRNA, ASO, aptamer hybrids Peptide orientation and linker spacing can affect accessibility. [RGD]

Targeting note: Targeting ligands should be selected around receptor biology, linker chemistry, oligonucleotide modality, conjugate stoichiometry and release QC requirements.

Cellular Uptake at a Glance

Best forCellular internalization
Common usesiRNA • ASO • SSO
Design focusHydrophobicity balance
QC focus Purity + solubility
Uptake Enhancer Primary Function Common Oligo Fit Design & Manufacturing Note Code
Cholesterol Hydrophobic uptake enhancement and membrane association siRNA, ASO, antagomir, miRNA tools Placement and spacer length influence solubility, uptake and purification. [Chol]
PC-Cholesterol Membrane interaction with phosphocholine context RNAi and ASO delivery research Useful when cholesterol display and lipid context need tuning. [PC-Chol]
Fatty Acids Hydrophobic anchoring and membrane association ASO, siRNA, extrahepatic delivery exploration Stearic, palmitic and oleic acid formats may change solubility and biodistribution. [SA]/[PA]/[OA]
2′-O-Lipidated Nucleosides Internal lipid placement for delivery tuning siRNA, ASO, advanced RNA constructs Includes C16, C18 and C18:1 lipidated nucleoside strategies. [C16]/[C18]
Diacylglycerol (DAG) Lipid anchor and trafficking support RNAi and advanced oligonucleotide constructs Hydrophobicity should be balanced against purification and formulation needs. [DAG]
CPP Peptides Cell penetration and intracellular entry ASO, SSO, siRNA, peptide-oligo conjugates TAT, R9, penetratin and custom CPPs may require peptide-oligo conjugation review. [CPP]
NLS Peptides Nuclear localization support SSO, steric-blocking ASO, nuclear-targeting systems Useful when nuclear accumulation is required for mechanism. [NLS]
Ceramide / Phosphatidylethanolamine Endolysosomal trafficking and membrane interaction Exploratory delivery constructs Plan analytical strategy for hydrophobic conjugates early. [Cer]/[PE]

Uptake note: Hydrophobic modifications can increase cellular association but may also affect solubility, aggregation, purification and formulation. Balance delivery gain against manufacturability.

PK & Biodistribution at a Glance

Best for Systemic exposure
Common useASO • siRNA • Conjugates
Design focusCirculation + solubility
QC focusMass + conjugate profile
PK Modifier Primary Function Common Oligo Fit Design & Manufacturing Note Code
Short PEG / TEG Spacer, solubility and conjugate geometry Most oligo conjugate formats Used to separate targeting ligand from oligo backbone while improving handling. [TEG]/[PEG]
Longer PEG Hydrodynamic size, solubility and circulation tuning ASO, aptamer, antibody-oligo conjugates May require careful purification and mass/size confirmation. [PEGn]
Albumin-Binding Tag Half-life extension through serum albumin interaction ASO, siRNA, advanced conjugates Useful when systemic exposure and reduced clearance are design goals. [ABP]
Tocopherol Lipophilic distribution and robustness support siRNA, ASO, antagomir-like constructs Can affect biodistribution and purification due to hydrophobicity. [Toco]
Squalene Self-assembly and particle-like behavior Advanced conjugate and formulation research Evaluate formulation, solubility and analytical method development. [SQL]
DHA / EPA Fatty-acid biodistribution tuning Oligonucleotide delivery research Useful for exploring lipid-mediated exposure and tissue distribution. [DHA]/[EPA]
High-Molecular-Weight Carriers Circulation and payload density Multivalent or carrier-based systems Requires custom conjugation strategy and orthogonal QC planning. [Carrier]
Formulation-Compatible Handles Buffer, solubility and downstream assembly support Conjugated ASO / siRNA / aptamer systems Useful when delivery modification must integrate into LNP, polymer or custom formulation workflows. [Handle]

PK note: PK modifiers are most useful when combined with a defined administration route, formulation plan, tissue target and release-testing package.

Advanced Systems at a Glance

Best forNext-generation delivery
Common useTherapeutic R&D
Design focusValency + release
QC focusStructure confirmation
Advanced System Primary Function Common Oligo Fit Design & Manufacturing Note Code
Aptamer-siRNA Chimera Receptor targeting plus RNAi payload Cell-specific RNAi research Requires aptamer folding, linker placement and duplex integrity review. [Apt-siRNA]
Antibody-Oligo Conjugate Cell-specific delivery through antibody recognition ASO, siRNA, payload and detection systems May require antibody modification, oligo handle selection and conjugate ratio analysis. [AOC]
Dual-Ligand Conjugate Two targeting or uptake motifs in one construct Advanced delivery research Useful when avidity, cell targeting or internalization requires multi-ligand design. [Dual-Lig]
Branched Oligonucleotide Delivery System Higher valency and geometry control ASO, siRNA, aptamer or multimeric oligos Doubler, trebler and brancher designs require custom synthesis planning. [Doubler]/[Trebler]
Drug-Oligo Conjugate Oligo as targeting, payload or hybrid therapeutic element Aptamer-drug, ASO-drug, probe-drug constructs Can include DOX, CPT, MTX or custom payloads with cleavable linkers. [Drug-Oligo]
Cleavable Linker Systems Controlled payload or ligand release Conjugated ASO, siRNA, aptamer and drug-oligo systems Disulfide, hydrazone, Val-Cit-PAB and photocleavable linkers available for feasibility review. [SS]/[Hyd]/[VC]
Dendrimer / PAMAM Systems High payload density and multivalent display Advanced delivery and assay systems Requires custom analytical strategy for polydispersity and conjugate profile. [PAMAM]
Custom Bioconjugation Program Project-specific delivery architecture ASO, siRNA, aptamer, RNA and hybrid constructs Use when the ligand, linker or architecture is not a standard catalog configuration. [Custom]

Advanced systems note: Complex conjugates should be designed with analytical feasibility in mind: identity, purity, conjugate ratio, branch integrity, linker cleavage and final formulation should be planned before scale-up.

Delivery Strategy Comparison

Fast Comparison: Uptake, Targeting, PK and Complexity

Use this comparison table as a fast decision guide. Final selection should be based on modality, sequence, target tissue, route of administration, linker design, purification and analytical requirements.

Oligonucleotide Delivery Strategy Comparison

Ratings are practical design-screening guides, not universal performance claims. Actual performance depends on sequence, chemistry pattern, ligand placement, formulation and biological model.

Strategy Uptake Targeting PK / Exposure Complexity Best-Fit Use
GalNAc ★★★ ★★★★★ ★★★ ★★ Hepatocyte targeting for ASO or siRNA programs.
Cholesterol / Lipids ★★★★★ ★ ★★ ★ Uptake enhancement and membrane association.
CPP Peptides ★★★★★ ★ ★ ★★ Cell penetration, SSO/ASO delivery exploration and intracellular delivery research.
PEG / TEG ★ ★ ★★★★★ ★★ Spacer design, solubility, circulation and conjugate geometry.
Albumin Binder ★★ ★ ★★★★★ ★★★ Half-life extension and systemic exposure tuning.
Aptamer ★★★ ★★★★★ ★★★ ★★★★ Programmable receptor targeting and aptamer-siRNA or aptamer-drug systems.
Antibody-Oligo ★★★ ★★★★★ ★★★★★ ★★★★★ Cell-specific targeting where antibody specificity and conjugate analytics are needed.
Cleavable Linker ★★ ★★ ★★ ★★★★ Payload release, intracellular trigger designs and conjugate mechanism studies.
Application-Centered Delivery Design

Tissue Targeting Applications

A delivery chemistry should be chosen around the intended biological application. These application tabs help connect ligand choice with tissue, cell type and oligonucleotide modality.

Common delivery approaches for hepatocyte-targeted oligonucleotides.

GalNAc-siRNA ASGPR-mediated hepatocyte uptake for liver-focused RNAi research and therapeutic development.
GalNAc-ASO / Gapmer Ligand-directed ASO or gapmer constructs for hepatocyte targeting and systemic dosing studies.
Cholesterol / Lipid Tuning Hydrophobic conjugates may support uptake and biodistribution studies depending on chemistry and route.

Representative strategies for tumor-targeted oligonucleotide delivery.

Aptamer Targeting Receptor-specific aptamers can be paired with siRNA, ASO or payload systems for tumor-cell research.
Antibody-Oligo Conjugates Antibody targeting can support cell-selective delivery strategies and advanced conjugate programs.
Folate / RGD Systems Folate and integrin-binding peptides can be considered for receptor-positive tumor models.

Representative strategies for immune-cell-directed oligonucleotide delivery.

Mannose Targeting Mannose receptor targeting can support macrophage and dendritic-cell focused delivery studies.
Antibody Targeting Antibody-oligo conjugates can support immune-cell marker-driven targeting strategies.
CPP / Peptide Delivery Peptide conjugates can be explored when internalization is a key bottleneck.

Emerging strategies for CNS and extrahepatic oligonucleotide delivery.

Angiopep-2 / Receptor Strategies Receptor-mediated transport strategies can be explored for brain-delivery research workflows.
RVG29 / Neuron Targeting Neuron-targeting peptide conjugates may be evaluated for research-stage delivery programs.
Lipid and Carrier Systems Lipidated or carrier-enabled oligonucleotides may support emerging extrahepatic delivery studies.
Custom Conjugation & Engineering

Custom Delivery Architecture Support

Bio-Synthesis can support customer-supplied designs and project-specific delivery architectures, including custom linkers, multivalent ligands, dual-ligand systems and complex oligonucleotide bioconjugates.

Lnk

Custom Linkers

PEG/TEG spacers, cleavable linkers, non-cleavable linkers, click handles and redox- or pH-sensitive release systems.

Val

Multivalent Display

Doubler, trebler, branched and scaffolded oligonucleotide constructs for avidity and geometry control.

BioC

Bioconjugation

Peptide, lipid, aptamer, antibody, small-molecule, drug and protein-oligonucleotide conjugation strategies.

QC

Conjugate Analytics

LC-MS, HPLC/UPLC, purity, identity, conjugate confirmation, branch integrity and project-specific documentation.

Manufacturing & Analytical Support

Quality and QC Built Around Delivery-Modified Oligos

Delivery-modified oligonucleotides often require more than standard desalting and mass confirmation. Hydrophobicity, conjugate ratio, linker stability, branch structure and formulation compatibility should be considered early.

QMS

Delivery-Modified Oligonucleotide Manufacturing Platform

Bio-Synthesis supports custom synthesis, conjugation, purification, analytical characterization and documentation for delivery-enabled oligonucleotide programs.

ISO 9001:2015 Quality management system
ISO 13485:2016 Medical-device quality framework
Analytical QC LC-MS, HPLC/UPLC, purity and identity
Custom Programs Confidential ligand, linker and conjugate support

Oligonucleotide Delivery & Targeting FAQ

FAQ

Which oligonucleotide delivery modification should I choose?
Start with the delivery objective. GalNAc is commonly used for hepatocyte targeting, cholesterol and lipid anchors improve uptake, PEG and albumin-binding tags support exposure and solubility, and aptamers or antibodies support cell-specific targeting.
Can Bio-Synthesis conjugate delivery ligands to ASO or siRNA?
Yes. Bio-Synthesis supports ligand, lipid, peptide, PEG, aptamer, antibody and custom bioconjugation strategies for ASO, siRNA, RNA and advanced oligonucleotide constructs.
Do hydrophobic delivery modifications affect purification?
Yes. Cholesterol, fatty acids, lipids and highly hydrophobic conjugates can affect solubility, chromatographic behavior and final formulation. Purification strategy should be selected early.
Can the delivery ligand be placed at the 5′ or 3′ end?
Often yes, depending on the modality, mechanism and required handle. Many designs use terminal placement with a spacer, but internal or branched placement can be reviewed for custom constructs.
Can you support cleavable linkers?
 Yes. Cleavable disulfide, hydrazone, enzyme-sensitive, photocleavable and custom linker systems can be reviewed based on payload, oligo format and release mechanism.
What information is needed for a quote?
 Provide sequence, modality, ligand or delivery chemistry, attachment position, linker preference, scale, purification, QC requirements, formulation format and application details.
More FAQ'sAll FAQ's
Before Requesting a Quote

Information Helpful for Delivery-Modified Oligos

Modality ASO, siRNA, aptamer, RNA
Sequence 5′→3′ and chemistry pattern
Ligand GalNAc, lipid, peptide, aptamer
Linker PEG, cleavable, click, custom
Scale nmol, µmol, mg, gram
QC LC-MS, HPLC/UPLC, CoA
Contact & Quote Request

Need help selecting or manufacturing a delivery-enabled oligo?

Share your sequence, target tissue, oligonucleotide modality, delivery ligand, linker strategy, conjugation position, scale, purification and QC requirements. Bio-Synthesis can help evaluate manufacturability and build a delivery-modified oligonucleotide workflow around your program.
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)
Del

Delivery Strategy Review

Choose targeting, uptake, PK or advanced conjugate systems based on application and manufacturability.

Targeting Uptake PK Release
QC

Conjugate Package

Purification, LC-MS, analytical purity, conjugate confirmation, labeling and documentation support.

HPLC/UPLC LC-MS CoA Custom QC
Recommended Reading

Recommended Reading & Literature References

Use this section to support scientific credibility while keeping the commercial message focused on delivery strategy, conjugation and manufacturability.

  1. Juliano RL. The delivery of therapeutic oligonucleotides. Nucleic Acids Research. 2016;44(14):6518–6548.
  2. Crooke ST, Wang S, Vickers TA, Shen W, Liang XH. Cellular uptake and trafficking of antisense oligonucleotides. Nature Biotechnology. 2017;35:230–237.
  3. Roberts TC, Langer R, Wood MJA. Advances in oligonucleotide drug delivery. Nature Reviews Drug Discovery. 2020;19:673–694.
  4. Nair JK, Willoughby JLS, Chan A, et al. Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi activity. Journal of the American Chemical Society. 2014;136(49):16958–16961.
  5. Wolfrum C, Shi S, Jayaprakash KN, et al. Mechanisms and optimization of in vivo delivery of lipophilic siRNAs. Nature Biotechnology. 2007;25:1149–1157.
  6. Zhou J, Rossi J. Aptamer-targeted cell-specific RNA interference. Silence. 2010;1:4.
  7. Springer AD, Dowdy SF. GalNAc-siRNA conjugates: leading the way for delivery of RNAi therapeutics. Nucleic Acid Therapeutics. 2018.
  8. Khvorova A. Oligonucleotide therapeutics — a new class of cholesterol and ligand conjugates. Nature Biotechnology. 2017.

Bio-Synthesis-Cited Publication Example

IGF1R-targeted delivery of a bridged nucleic acid oligonucleotide for triple-negative breast cancer. NAR Cancer, 2025. Your ASO page reference notes that BNA-DNA-BNA gapmer phosphorothioates and peptide conjugates were assembled using oligonucleotide synthesis and click chemistry by Bio-Synthesis, Inc., Lewisville, TX. This is a strong delivery-relevant citation because it connects bridged nucleic acid chemistry, targeted delivery and cancer application.

Suggested page note: Literature references are provided for scientific background. Final delivery-modified oligonucleotide design should be evaluated within the sequence, modality, tissue target, linker chemistry, purification method, analytical QC and application model.

Why Choose Bio-Synthesis

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Greetings Researchers,

Please be advised that any information, guidelines, writeups, 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 designs of the products intended for their experiments before submitting
their designs to Biosynthesis for review of production feasibility.
Thank you for your understanding.

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