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Lipid-Modified Oligonucleotides for Delivery & Cellular Uptake

Custom cholesterol, fatty acid, tocopherol, GalNAc-lipid, phospholipid and PEG-lipid oligonucleotide conjugates designed to improve cellular uptake, membrane interaction, tissue distribution, pharmacokinetics and formulation performance for DNA, RNA, antisense, siRNA and therapeutic research workflows.

Cholesterol • Fatty Acids • Tocopherol DSPE • DSPE-PEG • Ionizable Lipids GalNAc-Lipid • Lipid-siRNA • Lipid-ASO HPLC/SEC • ESI-MS/MALDI • Endotoxin
Discuss a Lipid-Oligo Design Explore Lipid Conjugates
Overview Delivery Strategy Design Matrix Modification Guide Applications Related Services FAQ Contact
Scientific Overview

Lipid-Modified Oligonucleotides for Delivery, Uptake and Formulation Research

Bio-Synthesis provides custom lipid-modified DNA and RNA oligonucleotides, including ASOs, siRNA, aptamers, probes and other nucleic-acid constructs. Sterols, saturated and unsaturated fatty acids, phosphatidylethanolamine lipids, PEG-lipids and vitamin-derived lipids can be used to influence membrane association, cellular uptake, serum-protein interaction, biodistribution, circulation and formulation behavior.

Performance depends on the complete molecular architecture—not simply the lipid name. Lipid class, terminal or internal placement, linkage, spacer, oligonucleotide modality, incorporation route, purification strategy and formulation conditions should be planned together. Lipids may also be combined with GalNAc, peptides, fluorophores, biotin or bioorthogonal handles when multifunctional delivery or analytical readouts are required.

Design principle: begin with the biological or formulation objective, then select the lipid architecture, placement and incorporation route that preserve oligonucleotide function while providing the required delivery behavior.

Lipid-Oligo Entry Through the Lipid Bilayer
uptake
lipid anchor supports membrane association
Lipid anchorBilayer interactionCellular uptake
Lipid & Delivery Conjugation Platforms

Representative Conjugation Strategies for Delivery, Targeting and Formulation

⌕ Click to Enlarge
Representative lipid and delivery conjugation platforms
Mem

Direct Membrane Association

Cholesterol, tocopherol and fatty-acid anchors increase hydrophobic association with cell membranes, model bilayers and membrane-derived systems.

Alb

Serum-Protein Interaction

Selected long-chain lipids can interact with albumin or other circulating proteins, influencing exposure, distribution and pharmacokinetic behavior.

LNP

Particle & Liposome Anchoring

DSPE, DOPE, DPPE and PEG-lipids support presentation on liposomes, micelles, lipid nanoparticles and other formulated delivery systems.

Multi

Targeted & Multifunctional Delivery

Lipid anchors can be integrated with GalNAc, peptides, reporters or affinity handles when receptor targeting, tracking or surface display is required.

Interactive Research Objective Selector

Choose a Lipid Strategy by Research Objective

Select the closest project goal to compare recommended lipid strategies, compatible oligonucleotide formats, incorporation routes, and practical design considerations. These are starting recommendations; final selection depends on sequence, placement, formulation, target system, and analytical requirements.

Recommended Starting Strategy

Improve Cellular Uptake

Use a lipophilic anchor that increases membrane and serum interaction while preserving oligonucleotide solubility, duplex behavior, and productive intracellular delivery.

Recommended Lipids
Best-Fit Oligo Formats
Typical Architecture & Route
Key Design Considerations
    TIP
    Bio-Synthesis Design Guidance

    Lipid Modification Library

    Lipid Chemistry & Incorporation Guide

    Select a lipid family to compare representative modifiers, intended function, preferred incorporation route, and typical oligonucleotide applications. The recommended route depends on reagent availability, lipid stability, conjugation position, spacer design, and purification requirements.

    How should I interpret "phosphoramidite available"?
    Terminal Modifier Amidite
    Terminal lipid incorporation

    A dedicated lipid modifier amidite introduces the lipid at the 5′ terminus during automated synthesis. A related functionalized CPG may be used for a defined 3′ lipid.

    Examples: palmitamido-C6, stearamido-C7, cholesteryl-TEG and tocopherol-TEG.

    Modified Nucleoside Amidite
    Internal site-specific lipid incorporation

    A lipid chain is built into a modified nucleoside monomer and placed at a selected nucleotide position during synthesis.

    Examples: 2′-O-C16 and 2′-O-C22 nucleoside phosphoramidites.

    These architectures create different linkages and placements. A terminal C16 conjugate and an internal 2′-O-C16 modification should therefore be treated as separate designs when selecting reagents, quoting, purifying, and documenting the final oligonucleotide.

    Representative single, dual, and triple saturated fatty acid siRNA conjugates using myristic and docosanoic acid architectures
    ⌕ Click to Enlarge
    Representative Single-, Dual-, and Multi-Lipid Architectures. Illustrative myristic-acid and docosanoic-acid siRNA conjugates showing increasing lipid valency.
    Primary use

    uptake, albumin interaction, and membrane anchoring

    Route

    amidite, CPG, or post-synthetic conjugation

    Design focus

    chain length, lipid valency, spacer, and placement

    Watch

    aqueous solubility, aggregation, and purification complexity

    Design principle: increasing lipid valency may strengthen membrane or protein interactions, but it can also reduce aqueous solubility and increase chromatographic complexity. Single-, dual-, and triple-lipid designs should be evaluated as distinct architectures.
    Lipid / Architecture Code Placement Available Route Preferred Method Typical Application
    Lauric Acid (C12) Terminal Conjugate [C12] Usually 5′ or 3′ Post-Synthetic Custom Amidite Possible Amide coupling unless a validated project-specific reagent is available Albumin interaction, circulation, and lipid SAR studies
    Myristic Acid (C14) Terminal Conjugate [C14] Usually 5′ or 3′ Post-Synthetic Custom Amidite Possible Activated fatty-acid coupling for most projects ASO and siRNA uptake screening
    Palmitamido-C6 / Palmitate (C16) [C16] 5′ by amidite; 3′ by CPG; terminal post-conjugation also possible Phosphoramidite CPG Post Direct terminal incorporation when the validated reagent fits the design C16-ASO, C16-siRNA, and extrahepatic delivery studies
    2′-O-C16 Nucleoside Modification [2′-O-C16] Internal or selected terminal nucleotide position Nucleoside Phosphoramidite Direct automated synthesis using the appropriate 2′-O-C16 A, C, G, or U monomer Site-specific lipophilic modification in siRNA and therapeutic RNA designs
    Stearamido-C7 / Stearate (C18) [C18] 5′ by amidite; 3′ by CPG where available; post-conjugation also possible Phosphoramidite CPG Post Direct terminal incorporation when a validated stearamido reagent is appropriate Albumin binding, uptake, and pharmacokinetic tuning
    Arachidic Acid (C20) Terminal Conjugate [C20] Usually terminal Post-Synthetic Custom Amidite Possible Post-synthetic coupling unless a validated custom reagent is supplied High-lipophilicity and membrane-retention studies
    Behenic / Docosanoic Acid (C22) Terminal Conjugate [C22] Usually terminal Post-Synthetic Custom Amidite Possible Post-synthetic coupling for a true terminal fatty-acid conjugate Advanced lipid SAR and strong hydrophobic anchoring
    2′-O-C22 Nucleoside Modification [2′-O-C22] Internal or selected nucleotide position Nucleoside Phosphoramidite Direct automated synthesis using 2′-O-C22-modified nucleoside monomers Site-specific extrahepatic delivery designs in siRNA and dsRNA
    Representative single, dual, and triple unsaturated fatty acid siRNA conjugates using DHA and EPA architectures
    ⌕ Click to Enlarge
    Representative Mono-, Di-, and Multi-Lipid Unsaturated Fatty Acid Architectures. Illustrative DHA and EPA siRNA conjugates showing increasing lipid valency.
    Primary use

    membrane interaction, fluidity, uptake, and distribution studies

    Route

    usually post-synthetic conjugation

    Design focus

    unsaturation level, lipid valency, spacer, and placement

    Watch

    oxidation, storage stability, solubility, and purification

    Design principle: unsaturated lipids can alter membrane interaction and biodistribution, while higher unsaturation may increase oxidative sensitivity. DHA and EPA conjugates require route, handling, and storage conditions matched to the final architecture.
    Lipid Code Function Available Route Preferred Method Typical Application
    Oleic Acid (C18:1) [C18:1] Monounsaturated lipid supporting membrane interaction and fluidity Post-Synthetic Amide coupling to amino oligo Membrane insertion and uptake studies
    Linoleic Acid (C18:2) [C18:2] Polyunsaturated lipid for delivery and hydrophobicity screening Post-Synthetic Activated lipid coupling under controlled conditions Lipid SAR and uptake optimization
    α-Linolenic Acid (C18:3) [ALA] Omega-3 lipid for exploratory delivery and tissue-distribution studies Post-Synthetic Amide or click-mediated conjugation Exploratory lipid-delivery research
    Arachidonic Acid (C20:4) [ARA] Highly unsaturated lipid for membrane and signaling-related studies Post-Synthetic Case-specific coupling with oxidation control Membrane biology and delivery screening
    Eicosapentaenoic Acid [EPA] Omega-3 lipid for uptake and biodistribution research Post-Synthetic Activated ester or click conjugation siRNA and lipid SAR studies
    Docosahexaenoic Acid [DHA] Polyunsaturated lipid associated with membrane interaction and tissue distribution Post-Synthetic Post-synthetic conjugation with stability controls DHA-siRNA and delivery research
    Representative phosphatidylethanolamine oligo conjugate structures including PE, DHPE, soy PE, DOPE, and DSPE
    ⌕ Click to Enlarge
    Representative PE Conjugate Structures
    Primary use

    liposomes, membranes and LNP display

    Route

    post-synthetic conjugation

    Design focus

    PEG length and reactive terminus

    Watch

    solubility and formulation behavior

    Lipid Code Function Available Route Preferred Method Typical Application
    DOPE [DOPE] Unsaturated PE lipid supporting membrane fusion and liposome systems Post-Synthetic Reactive DOPE derivative coupled to oligo handle Liposomes, membrane probes and formulation research
    DPPE [DPPE] Saturated PE lipid for stable bilayer insertion Post-Synthetic Amide, maleimide or click coupling Membrane display and particle functionalization
    DSPE [DSPE] Long-chain PE anchor commonly used in liposomes and LNPs Post-Synthetic DSPE-PEG reactive derivative preferred LNP, liposome and micelle systems
    DSPE-PEG2000 [DSPE-PEG2000] Combines membrane anchoring with PEG spacing and surface display Post-Synthetic Maleimide, NHS or click-functional DSPE-PEG LNP-facing oligos and nanoparticle display
    DSPE-PEG-Maleimide [DSPE-PEG-Mal] Thiol-reactive PEG-lipid for selective oligo attachment Post-Synthetic 5′-thiol oligo + maleimide lipid Surface display and nanoparticle conjugation
    DSPE-PEG-NH2 [DSPE-PEG-NH2] Amine-functional PEG-lipid for activated coupling strategies Post-Synthetic Activated carboxyl or heterobifunctional linker Custom lipid-oligo architectures
    Representative single, dual, and triple saturated fatty acid siRNA conjugates using myristic and docosanoic acid architectures
    ⌕ Click to Enlarge
    Representative Single-, Dual-, and Multi-Lipid Architectures. Illustrative myristic-acid and docosanoic-acid siRNA conjugates showing increasing lipid valency.
    Primary use

    uptake, albumin interaction, and membrane anchoring

    Route

    amidite, CPG, or post-synthetic conjugation

    Design focus

    chain length, lipid valency, spacer, and placement

    Watch

    aqueous solubility, aggregation, and purification complexity

    Design principle: increasing lipid valency may strengthen membrane or protein interactions, but it can also reduce aqueous solubility and increase chromatographic complexity. Single-, dual-, and triple-lipid designs should be evaluated as distinct architectures.
    Lipid / Architecture Code Placement Available Route Preferred Method Typical Application
    Lauric Acid (C12) Terminal Conjugate [C12] Usually 5′ or 3′ Post-Synthetic Custom Amidite Possible Amide coupling unless a validated project-specific reagent is available Albumin interaction, circulation, and lipid SAR studies
    Myristic Acid (C14) Terminal Conjugate [C14] Usually 5′ or 3′ Post-Synthetic Custom Amidite Possible Activated fatty-acid coupling for most projects ASO and siRNA uptake screening
    Palmitamido-C6 / Palmitate (C16) [C16] 5′ by amidite; 3′ by CPG; terminal post-conjugation also possible Phosphoramidite CPG Post Direct terminal incorporation when the validated reagent fits the design C16-ASO, C16-siRNA, and extrahepatic delivery studies
    2′-O-C16 Nucleoside Modification [2′-O-C16] Internal or selected terminal nucleotide position Nucleoside Phosphoramidite Direct automated synthesis using the appropriate 2′-O-C16 A, C, G, or U monomer Site-specific lipophilic modification in siRNA and therapeutic RNA designs
    Stearamido-C7 / Stearate (C18) [C18] 5′ by amidite; 3′ by CPG where available; post-conjugation also possible Phosphoramidite CPG Post Direct terminal incorporation when a validated stearamido reagent is appropriate Albumin binding, uptake, and pharmacokinetic tuning
    Arachidic Acid (C20) Terminal Conjugate [C20] Usually terminal Post-Synthetic Custom Amidite Possible Post-synthetic coupling unless a validated custom reagent is supplied High-lipophilicity and membrane-retention studies
    Behenic / Docosanoic Acid (C22) Terminal Conjugate [C22] Usually terminal Post-Synthetic Custom Amidite Possible Post-synthetic coupling for a true terminal fatty-acid conjugate Advanced lipid SAR and strong hydrophobic anchoring
    2′-O-C22 Nucleoside Modification [2′-O-C22] Internal or selected nucleotide position Nucleoside Phosphoramidite Direct automated synthesis using 2′-O-C22-modified nucleoside monomers Site-specific extrahepatic delivery designs in siRNA and dsRNA
    Representative single, dual, and triple saturated fatty acid siRNA conjugates using myristic and docosanoic acid architectures
    ⌕ Click to Enlarge
    Representative Single-, Dual-, and Multi-Lipid Architectures. Illustrative myristic-acid and docosanoic-acid siRNA conjugates showing increasing lipid valency.
    Primary use

    uptake, albumin interaction, and membrane anchoring

    Route

    amidite, CPG, or post-synthetic conjugation

    Design focus

    chain length, lipid valency, spacer, and placement

    Watch

    aqueous solubility, aggregation, and purification complexity

    Design principle: increasing lipid valency may strengthen membrane or protein interactions, but it can also reduce aqueous solubility and increase chromatographic complexity. Single-, dual-, and triple-lipid designs should be evaluated as distinct architectures.
    Lipid / Architecture Code Placement Available Route Preferred Method Typical Application
    Lauric Acid (C12) Terminal Conjugate [C12] Usually 5′ or 3′ Post-Synthetic Custom Amidite Possible Amide coupling unless a validated project-specific reagent is available Albumin interaction, circulation, and lipid SAR studies
    Myristic Acid (C14) Terminal Conjugate [C14] Usually 5′ or 3′ Post-Synthetic Custom Amidite Possible Activated fatty-acid coupling for most projects ASO and siRNA uptake screening
    Palmitamido-C6 / Palmitate (C16) [C16] 5′ by amidite; 3′ by CPG; terminal post-conjugation also possible Phosphoramidite CPG Post Direct terminal incorporation when the validated reagent fits the design C16-ASO, C16-siRNA, and extrahepatic delivery studies
    2′-O-C16 Nucleoside Modification [2′-O-C16] Internal or selected terminal nucleotide position Nucleoside Phosphoramidite Direct automated synthesis using the appropriate 2′-O-C16 A, C, G, or U monomer Site-specific lipophilic modification in siRNA and therapeutic RNA designs
    Stearamido-C7 / Stearate (C18) [C18] 5′ by amidite; 3′ by CPG where available; post-conjugation also possible Phosphoramidite CPG Post Direct terminal incorporation when a validated stearamido reagent is appropriate Albumin binding, uptake, and pharmacokinetic tuning
    Arachidic Acid (C20) Terminal Conjugate [C20] Usually terminal Post-Synthetic Custom Amidite Possible Post-synthetic coupling unless a validated custom reagent is supplied High-lipophilicity and membrane-retention studies
    Behenic / Docosanoic Acid (C22) Terminal Conjugate [C22] Usually terminal Post-Synthetic Custom Amidite Possible Post-synthetic coupling for a true terminal fatty-acid conjugate Advanced lipid SAR and strong hydrophobic anchoring
    2′-O-C22 Nucleoside Modification [2′-O-C22] Internal or selected nucleotide position Nucleoside Phosphoramidite Direct automated synthesis using 2′-O-C22-modified nucleoside monomers Site-specific extrahepatic delivery designs in siRNA and dsRNA
    Modification Guide

    Lipid Conjugate Product & Modification Selector

    The guide includes the live-site lipid list and expands it with additional common sterol, fatty acid, phospholipid, PEG-lipid, targeted lipid and multifunctional conjugates.

    Select a lipid-conjugate category to view modification options

    Cholesterol & Sterol Conjugates — practical first choices for uptake, membrane association and sterol-driven delivery studies.

    Best for
    uptake
    Design focus
    terminal spacing
    QC focus
    hydrophobic purity
    Watch
    solubility
    Category Lipid Conjugate Code Function Typical Application
    Sterol Cholesterol [Chol] Most common hydrophobic sterol; enhances uptake, membrane association and serum stability Cholesterol-siRNA, ASO, probes, uptake studies
    Sterol Cholesteryl TEG [Chol-TEG] Cholesterol with hydrophilic spacer to reduce steric hindrance Duplex-compatible lipid attachment and probe delivery
    Sterol Cholesterol CPG / 3′ Cholesterol [3′-Chol] Terminal cholesterol incorporation during solid-phase synthesis 3′ lipidated oligos and cholesterol-siRNA passenger strands
    Sterol Hydroxyprolinol Cholesterol [Hyp-Chol] Rigid sterol attachment architecture used in advanced oligo delivery designs Therapeutic research and conjugate SAR studies
    Sterol Cholesterol-PEG2000 [Chol-PEG2000] Combines sterol membrane affinity with PEG shielding Micelles, nanoparticle systems and circulation tuning
    Sterol Vitamin D3 [VitD3] Vitamin lipid with high hydrophobicity and potential tissue-specific activity Specialized uptake, membrane interaction and SAR projects

    Fatty Acid Conjugates — chain length and saturation can be tuned for hydrophobicity, membrane interaction and PK screening.

    Best for
    SAR
    Design focus
    C-chain length
    QC focus
    identity
    Watch
    aggregation
    Category Lipid Conjugate Code Function Typical Application
    Fatty Acid Lauric Acid (C12) [C12] Medium-chain lipid for moderate hydrophobicity Solubility-balanced uptake studies and lipid SAR
    Fatty Acid Myristic Acid (C14) [C14] Enhances membrane interaction and hydrophobicity Myristoylated siRNA/ASO models and uptake tuning
    Fatty Acid Palmitic Acid (C16) [C16] Improves lipophilicity and membrane anchoring C16 oligo conjugates, ASO and siRNA uptake
    Fatty Acid Stearic Acid (C18) [C18] Saturated fatty acid for hydrophobicity and PK tuning Long-chain lipid-ASO and uptake studies
    Fatty Acid Oleic Acid (C18:1) [C18:1] Unsaturated fatty acid that increases membrane interaction Membrane insertion and fluidity-sensitive applications
    Fatty Acid Linoleic Acid (C18:2) [C18:2] Polyunsaturated fatty acid for lipid SAR and uptake tuning Delivery screening and hydrophobicity optimization
    Fatty Acid Docosahexaenoic Acid (DHA) [DHA] Polyunsaturated lipid associated with fusion, membrane interaction and tissue distribution DHA-siRNA, micelles, LNPs or direct conjugation
    Fatty Acid Eicosapentaenoic Acid (EPA) [EPA] Polyunsaturated lipid for omega-3 delivery studies siRNA lipid SAR and uptake optimization
    Fatty Acid Arachidic Acid (C20) [C20] Long saturated chain with stronger hydrophobicity Membrane anchoring and high-lipophilicity designs
    Fatty Acid Docosanoic / Behenic Acid (C22) [C22] Very long chain fatty acid for strong hydrophobic interaction Advanced lipid SAR and high-retention membrane studies
    PEG-Lipid C16-PEG2000 [C16-PEG2000] Fatty-acid PEG lipid for micelle or nanoparticle delivery Micelles, lipid particles and formulation screens
    PEG-Lipid Stearic Acid-PEG [C18-PEG] C18 lipid with PEG spacer to improve circulation and solubility Long-circulation conjugates and formulation optimization

    Phospholipids, Glycerides and PEG-Lipids — designed for app-aso, micelles, liposomes, LNPs and surface display.

    Best for
    formulation
    Design focus
    PEG length
    QC focus
    SEC optional
    Watch
    formulation
    Category Lipid Conjugate Code Function Typical Application
    Phospholipid DSPE [DSPE] Phospholipid anchor used in liposomes and LNP systems Membrane insertion, liposome display and LNP formulation
    PEG-Phospholipid DSPE-PEG2000 [DSPE-PEG2000] Adds hydrophilicity and flexibility; common in LNPs LNPs, micelles, liposomes and vaccine platforms
    PEG-Phospholipid DSPE-PEG3400 / DSPE-PEG5000 [DSPE-PEG3400], [DSPE-PEG5000] Longer PEG shielding for steric stabilization and distance control Surface display, nanoparticle stabilization and spacer tuning
    Reactive PEG-Lipid DSPE-PEG-Maleimide [DSPE-PEG-Mal] Thiol-reactive PEG-lipid for post-synthetic conjugation Thiol-modified oligo coupling and nanoparticle display
    Reactive PEG-Lipid DSPE-PEG-Amine [DSPE-PEG-NH2] Amine-functional PEG-lipid for activated ester or crosslinker chemistry Custom lipid-oligo conjugation and formulation studies
    Glyceride Diacylglycerol (DAG) Analogs [DAG] Membrane anchoring and bilayer integration Liposomes, LNPs and vaccine delivery platforms
    Glyceride Triacylglycerol (TAG) Analogs [TAG] Enhances lipid bilayer integration and hydrophobicity Lipid bilayer models and formulation screening
    Dialkyl Lipid 1,2-Di-O-octadecyl-sn-glyceryl (DOG) [DOG] Long-chain alkyl ether for strong hydrophobic interaction Membrane anchoring and hydrophobic conjugate studies
    Phospholipid Phosphatidylcholine Derivatives [PC-Lipid] Phospholipid-like membrane anchor Membrane models, liposomes and LNP compatibility studies

    Advanced Targeted and Multifunctional Lipid Conjugates — combine delivery lipids with targeting, imaging, affinity or formulation functions.

    Best for
    targeted delivery
    Design focus
    orthogonal chemistry
    QC focus
    full conjugate
    Watch
    complexity
    Category Lipid Conjugate Code Function Typical Application
    Vitamin-Lipid Vitamin E / α-Tocopherol [VitE], [Toc] Lipophilic antioxidant; supports uptake and tissue-distribution studies Tocopherol-siRNA, ASO and therapeutic delivery research
    Vitamin-Lipid Tocopherol-TEG [Toc-TEG] Tocopherol with hydrophilic spacer to improve accessibility Duplex-compatible tocopherol conjugates and uptake tuning
    Targeted Lipid GalNAc-Lipid [GalNAc-Lipid] Combines liver targeting and membrane affinity ASO/siRNA liver delivery research
    Targeted Lipid TriGalNAc-Lipid [TriGalNAc] Multivalent hepatocyte targeting with lipid functionality High-affinity liver uptake and therapeutic oligo research
    Ionizable Lipid Ionizable Lipid Conjugates [Ionizable-Lipid] pH-responsive lipid design for endosomal escape studies LNP-compatible oligos and intracellular delivery optimization
    Custom LNP Lipid Custom LNP-Compatible Lipids [LNP-Lipid] Tailored lipid architecture for particle formulation LNP, micelle, liposome and formulation development
    Multifunctional Lipid-Fluorophore Conjugates [Lipid-Dye] Combines uptake lipid with optical readout Cell uptake tracking, imaging and biodistribution studies
    Multifunctional Lipid-Biotin Conjugates [Lipid-Biotin] Combines hydrophobic anchor with affinity capture Pull-down, bead display, surfaces and membrane models
    Multifunctional Lipid-Peptide Conjugates [Lipid-Peptide-Oligo] Combines lipid delivery with peptide targeting or uptake motifs Multifunctional delivery and targeting studies
    Multifunctional Lipid-GalNAc Conjugates [Lipid-GalNAc] Combines receptor targeting with hydrophobic delivery modulation Liver-targeted and multifunctional therapeutic oligo research
    Architecture Lipid-siRNA / Lipid-ASO / Lipid-sgRNA [Lipid-RNA] Application-specific lipid conjugate format RNAi, antisense, CRISPR and delivery platform development

    Need a lipid not listed? Bio-Synthesis can evaluate custom lipid reagents, internal codes, vendor references or application-specific lipid architectures for feasibility, synthesis route, purification and analytical QC.

    Application-Centered Design

    Match Lipid Chemistry to the Oligo Modality

    The best lipid depends on oligo type, target tissue, formulation plan, readout and whether delivery is direct or carrier-assisted.

    Recommended lipids

    Cholesterol, C16/C18 fatty acids, GalNAc-lipid, tocopherol and PEG-lipid options.

    Design Focus

    Place lipids at termini when possible; add PEG spacers to preserve hybridization and reduce steric effects.

    Readout

    Cell uptake, target knockdown, serum stability, PK/PD and tissue exposure.

    Recommended lipids

    Cholesterol-siRNA, DHA-siRNA, tocopherol-siRNA, GalNAc-lipid siRNA and lipid-DsiRNA constructs.

    Design Focus

    Confirm guide/passenger placement, duplex activity and any spacer needed between lipid and RNA duplex.

    Readout

    Cellular uptake, RISC activity, target mRNA/protein knockdown and biodistribution.

    Recommended lipids

    DSPE, DSPE-PEG, DAG, TAG, ionizable lipids and custom LNP-compatible anchors.

    Design Focus

    Align lipid anchor, PEG length and oligo placement with particle formulation and release goals.

    Readout

    Particle incorporation, size/PDI, release, potency and formulation stability.

    Recommended lipids

    Lipid-fluorophore oligos, lipid-biotin oligos, phospholipid probes and membrane-anchor oligos.

    Design Focus

    Balance hydrophobic anchoring with fluorescent signal, background, and surface or membrane compatibility.

    Readout

    Microscopy, flow cytometry, pull-down, surface display or membrane model assay.
    Analytical QC & Delivery

    QC, Release Data and Delivery Formats

    Lipid-oligo conjugates need stronger analytical attention than routine oligos because hydrophobic conjugates can affect solubility, purification, aggregation and assay behavior.

    QC & Deliverables

    QC packages may include ESI-MS or MALDI identity, HPLC purity, optional SEC for larger or aggregating constructs, OD/µmol yield, lipid identity, spacer length, placement, and supporting chromatograms or spectra.

    HPLC / RP-HPLC

    Purity assessment and separation of hydrophobic conjugates from failed or unconjugated material.

    ESI-MS / MALDI

    Identity confirmation of oligo, lipid, spacer and conjugate mass where compatible.

    SEC Optional

    Useful for large constructs, micelle-forming conjugates, aggregation checks and formulation studies.

    Release Add-ons

    Endotoxin, moisture, residual solvents, stability, salt/counterion and custom documentation.

    Delivery Formats

    Lyophilized tubes or plates, custom labels, barcodes, normalized amounts and digital documentation.

    Handling Notes

    Hydrophobic conjugates may require special reconstitution, vortexing, warming, sonication or formulation buffer.

    Reorder Traceability

    Release data, chromatograms and spectra can be archived to support repeat manufacturing.

    FAQ

    How should lipid-modified oligonucleotides be stored?
    For long-term storage, lipid-modified oligonucleotides are typically stored dry at −20°C in a light-protected environment. Avoid repeated freeze-thaw cycles. Storage recommendations may vary by lipid chemistry, conjugate architecture and formulation.
    How should lipid-modified oligonucleotides be reconstituted?
    Most lipid-conjugated oligonucleotides can be reconstituted in nuclease-free water, TE buffer, PBS or formulation-specific buffers. Highly hydrophobic conjugates may require gentle warming, extended mixing, sonication, a small amount of compatible organic co-solvent or specialized formulation conditions.
    Are lipid-modified oligos harder to dissolve than standard oligos?
    Yes. Hydrophobic lipids such as cholesterol, tocopherol and long-chain fatty acids can reduce aqueous solubility or promote self-association. Start with the recommended concentration and buffer, then adjust mixing, temperature or formulation as needed.
    What QC is recommended for lipid-oligo conjugates?
    HPLC or RP-HPLC purity and ESI-MS/MALDI identity are recommended. SEC, endotoxin, residual solvent, moisture, stability and custom release documentation can be added depending on the application.
    Will lipid conjugation change duplex stability or activity?
    It can. Lipids may introduce steric effects, hydrophobic aggregation or altered duplex behavior. PEG or TEG spacers are often used to preserve hybridization and reduce self-association.
    How do I choose 5′, 3′ or internal lipid placement?
    Terminal lipid placement is usually the easiest to synthesize, purify and interpret. Internal placement is possible but should be designed with spacers and piloted to confirm Tm, hybridization, duplex activity and functional potency.
    Which lipids are best for siRNA versus ASO?
    For siRNA, cholesterol, DHA, tocopherol, GalNAc-lipids and DSPE-PEG are common starting points depending on route and formulation. For ASO, cholesterol, C16/C18 fatty acids, tocopherol and GalNAc-lipid options are commonly evaluated for uptake and PK tuning.
    Can lipids be combined with GalNAc, dyes, peptides or biotin?
    Yes. Multifunctional lipid oligos can combine lipids with GalNAc, fluorescent dyes, peptides, biotin, PEG or bioorthogonal handles when spacing, chemistry and purification are planned carefully.
    More FAQ'sAll FAQ's
    Before Requesting a Quote

    Information Helpful for Caged Oligos

    Oligo Type
    DNA, RNA, ASO, siRNA
    Lipid
    Chol, C16, DSPE, GalNAc
    Placement
    5′, 3′, internal, duplex
    Spacer
    TEG, PEG, custom
    Scale
    nmol to gram
    QC
    HPLC, MS, SEC, endotoxin
    Contact & Quote Request

    Need help choosing a lipid conjugate?

    Share your sequence, modality, lipid type, placement, spacer preference, formulation plan, scale, purification grade, QC requirements, storage needs and delivery format. Bio-Synthesis can help recommend a practical lipid-oligo design path.
    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)

    Design Review

    Compare cholesterol, fatty acids, tocopherol, DSPE-PEG, GalNAc-lipids and custom lipid architectures.

    Chol C16 DSPE GalNAc

    QC & Handling Package

    Plan HPLC, MS, optional SEC, endotoxin, stability, storage and reconstitution instructions.

    HPLC MS SEC Storage
    Scientific Background & Recommended Reading

    Recommended Reading & Literature References

    1. Wolfrum C, et al. Mechanisms and optimization of in vivo delivery of lipophilic siRNAs. Nature Biotechnology. 2007.
    2. Nair JK, et al. Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing. Journal of the American Chemical Society. 2014.
    3. Juliano RL. The delivery of therapeutic oligonucleotides. Nucleic Acids Research.
    4. Springer AD, Dowdy SF. GalNAc-siRNA conjugates and related delivery technologies for RNA therapeutics.
    5. Khvorova A, Watts JK. The chemical evolution of oligonucleotide therapies of clinical utility. Nature Biotechnology.
    6. Juliano RL. Cellular uptake and intracellular trafficking of oligonucleotides. Molecular Pharmaceutics.

    Suggested page note: References are provided for scientific background. Final lipid-oligo design should be evaluated within the sequence, modality, lipid chemistry, spacer, formulation route, target tissue, solubility, purification and QC requirements.

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    Please be advised that any information, guidelines, write-ups, and oral/video/graphic content on our website are intended solely as general guidelines.
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