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Peptide–siRNA Conjugation Services

Site-defined peptide–oligonucleotide conjugates with controllable linker chemistry and fit-for-purpose analytics.

Enable controlled siRNA delivery using modular peptide conjugates for uptake, targeting, and endosomal escape—without reliance on lipid nanoparticle formulations.

Request a Quote Service options Chemistry
Overview Best for Schematic Attachment sites Chemistry Peptide types Cleavable vs non-cleavable Design rules QC FAQ Contact Reading

Overview

What is peptide–siRNA conjugation?

Peptide–siRNA conjugation covalently links a synthetic peptide (cell-penetrating, targeting, and/or endosomolytic) to an siRNA strand using a defined chemoselective linker. The goal is to improve cell entry, tissue targeting, and cytosolic delivery while preserving functional gene-silencing activity.

Compared with electrostatic “complexation,” a defined conjugate provides reproducible stoichiometry (often 1:1), cleaner structure–activity interpretation, and more consistent batch-to-batch performance.

In contrast to lipid nanoparticle (LNP) formulations, peptide–siRNA conjugates offer a chemically defined, single-component construct that simplifies characterization, reproducibility, and early-stage development workflows.

Why peptide–siRNA conjugates?
  • Defined 1:1 stoichiometry supporting reproducible manufacturing and interpretation
  • Reduced batch-to-batch variability compared with electrostatic complexation
  • Clear structure–activity relationships to support rational optimization
  • Modular architecture enabling controlled targeting, uptake, and endosomal escape
  • Well-aligned with translational development and regulatory expectations

siRNA molecules are highly anionic and generally show poor membrane permeability when administered alone. siRNA-peptide conjugation addresses this limitation by covalently attaching delivery peptides—such as cell-penetrating, targeting, or endosomolytic sequences—to siRNA through defined chemical linkers. This strategy improves cellular uptake and intracellular delivery while maintaining siRNA integrity and functional gene-silencing activity under defined chemical control.

At Bio-Synthesis, peptide–siRNA conjugates are prepared using site-defined conjugation chemistries and produced under rigorous quality control standards. Each construct is designed to maintain antisense strand functionality and is purified and characterized to ensure structural integrity, reproducibility, and application-ready performance.

Flexible Conjugation Chemistry Cleavable & non-cleavable Bench to Kilo Scale Production ISO 9001:2015/ISO 13845:2016 45+ Years of Expertise U.S. Facilities - Texas
Critical constraint (avoid costly failures)

Do not block the antisense 5′ end (RISC loading). When in doubt, attach to the sense strand at the 3′ or 5′ end.

Related services: Peptide Modifications, Peptide Bioconjugation, Click Chemistry Peptides, Cleavable Linker Peptides.

Best for

Targeted knockdown

Receptor/tissue-homing peptides + siRNA payload for selective delivery and mechanism studies.

CPP delivery

Improve uptake for hard-to-transfect cells and primary cell workflows.

Endosomal escape

pH-responsive / histidine-rich modules to improve functional cytosolic delivery.

Schematic

Schematic of peptide–siRNA conjugate showing peptide module, linker options, and siRNA duplex with sense/antisense strands and 5′/3′ ends.
Figure: Peptide module + linker + siRNA duplex. Common attachment is the sense strand at the 3′ or 5′ end.

Where the peptide is attached on siRNA

Attachment site Typical use Notes / risk
Sense strand 3′ end Most common for targeting peptides and CPPs Good default; preserves antisense 5′ for RISC loading
Sense strand 5′ end Alternative orientation for specific architectures Often fine; validate potency empirically
Antisense strand 3′ end Used when sense must remain unmodified Can work; avoid bulky attachment that interferes with RISC
Antisense strand 5′ end Generally avoided High risk: can block RISC loading and reduce knockdown
Request a Quote Choose chemistry

Linker & conjugation chemistry

Peptide–siRNA conjugates are formed via covalent attachment between functional groups on the siRNA (typically at the 3′ or 5′ terminus) and complementary handles on the peptide. Conjugation is performed using pre-activated crosslinkers that react selectively with thiol, amine, azide, or alkyne groups under controlled conditions.

Depending on the application, conjugates may incorporate stable linkers (e.g., triazole or thioether) for tracking and mechanistic studies, or cleavable linkers (e.g., disulfides) designed to release siRNA in the intracellular reducing environment. Linker selection is guided by delivery requirements, stability needs, and downstream biological performance.

Copper-free click (preferred for RNA)

Azide–DBCO / azide–BCN for clean, site-specific coupling.

  • RNA-friendly (avoids copper exposure)
  • High selectivity and reproducible conversions
  • Scales well for defined conjugates
Thiol–maleimide

Fast coupling using terminal thiols and maleimide handles.

  • Works well for prototypes and research builds
  • Consider stabilized maleimide designs for in-vivo work
  • Handle planning prevents multi-site mixtures
Amide coupling (advanced)

Activated ester / EDC routes when unique handles are available.

  • Useful when click handles are constrained
  • Requires strict control to avoid heterogeneity
  • Often paired with protected functional handles
Cleavable linkers (release designs)

Selected when cytosolic release is required to maximize knockdown.

  • Disulfide (reducible)
  • Enzyme-responsive spacers (project-dependent)
  • pH-labile designs (project-dependent)
Non-cleavable linkers

Preferred when stable linkage and tracking are the priority.

  • Stable thioether or triazole linkages
  • Reduced risk of premature release
  • Validate RISC compatibility case-by-case

Peptide–siRNA Conjugation Workflow

Workflow for peptide–siRNA conjugation including design, conjugation, purification, QC, and delivery
Typical workflow for peptide–siRNA conjugate synthesis and quality control.

This workflow supports research, preclinical, and translational programs with scalable conjugation and reproducible analytical control.

  • Design & Functionalization – Selection of siRNA strand, peptide sequence, and compatible functional handles.
  • Controlled Conjugation – Chemoselective coupling using pre-activated linkers under monitored conditions.
  • Purification – Removal of unreacted components by HPLC or size-exclusion chromatography.
  • Analytical Characterization – Confirmation by mass spectrometry, chromatography, and UV analysis.
  • Final Delivery – Lyophilized conjugate supplied with COA and analytical documentation.
Development considerations
  • Early selection of attachment site and linker chemistry simplifies downstream characterization and comparability.
  • Chemically defined conjugates support clearer structure–activity relationships than multicomponent delivery systems.
  • Cleavable versus non-cleavable linkers should be chosen based on the need for intracellular release versus construct stability.
  • Analytical strategies may evolve as programs progress from feasibility to translational studies.

Bio-Synthesis can align conjugation strategy, purification, and analytical depth to the intended stage of development.

Peptide types used in peptide–siRNA conjugates

Cell-penetrating peptides (CPPs)

Boost uptake across diverse cell types; often benefits from escape strategy.

  • Arg/Lys-rich sequences
  • Charge tuning to reduce aggregation
  • Spacer length to reduce sterics
Targeting peptides

Add receptor/tissue selectivity for targeted delivery studies.

  • Receptor-binding ligands
  • Tissue-homing motifs
  • Orientation-controlled conjugation
Endosomolytic modules

Improve functional delivery by boosting endosomal escape.

  • pH-responsive sequences
  • Histidine-rich designs
  • Multifunctional constructs
Practical default (first build)

Attach a delivery peptide to the sense strand 3′ using copper-free click, and consider a disulfide if intracellular release is required. Then tune spacer length and peptide charge to minimize aggregation.

Cleavable vs non-cleavable linkers

Cleavable
  • Disulfide: intracellular reduction-driven release
  • Enzyme-responsive spacers (application-dependent)
  • Acid-labile (pH-triggered) designs in some systems

Use when: you want cytosolic release to maximize functional knockdown.

Non-cleavable
  • Highest structural stability
  • Useful for tracking/uptake studies and mechanistic controls
  • May reduce activity if attachment interferes with RISC

Use when: stability is priority; validate activity empirically.

Design rules that prevent failures

Must-follow constraints
  • Do not block antisense 5′ end (RISC loading)
  • Prefer sense 3′/5′ conjugation for first builds
  • Use RNA-friendly chemistry; avoid copper carryover
  • Control peptide charge density to reduce aggregation
Optimization levers
  • Linker/spacer length to reduce sterics
  • Cleavability (release vs stable)
  • Peptide architecture: targeting vs CPP vs escape
  • Orientation and strand choice to preserve potency

Service options we support

Defined peptide handles
  • N-terminus / C-terminus
  • Cys / Lys orthogonal sites
  • Azide / alkyne / DBCO / BCN
Linker selection
  • Copper-free click
  • Thiol–maleimide
  • Disulfide (reducible)
  • Custom spacers (PEG / alkyl)
Formats delivered
  • Purified 1:1 conjugates
  • Matched controls (peptide-only / siRNA-only)
  • Small-scale feasibility → scale-up
What to share for the fastest recommendation

Send your siRNA strand design (sense/antisense + any 2′ modifications), peptide sequence, and intended biology. If you’re unsure, write: “Recommend best attachment site + linker.”

QC & typical deliverables

Standard QC
  • Purity profile (chromatography-based)
  • Identity and conjugation confirmation using mass-based and orthogonal analytical methods where applicable
  • COA + method summary
Conjugation efficiency
  • Conversion / residual starting-material check
  • Conjugation confirmation aligned to construct
  • Optional orthogonal methods (project-dependent)
When to add more

If your decision depends on stability or release behavior, tell us—methods can be aligned to it.

Exact QC approaches vary with siRNA chemistry (e.g., 2′ modifications), linker choice, and peptide properties.

FAQ

Where should a peptide be attached on siRNA?

Most programs attach to the sense strand (3′ or 5′) to preserve antisense 5′ function for RISC loading. Antisense 3′ can be used case-by-case; antisense 5′ is generally avoided.

Is copper-free click better than CuAAC for RNA?

Copper-free click avoids copper exposure and cleanup concerns, making it a strong default for oligonucleotide conjugation. CuAAC can work if copper is tightly controlled and removed.

Should I choose a cleavable disulfide linker?

Choose a disulfide when you want intracellular release to maximize functional delivery. If you need maximal stability for tracking or mechanistic controls, a non-cleavable linker may be sufficient.

What do you need to quote a peptide–siRNA conjugate?

Send sense/antisense sequences (and any 2′ modifications), attachment preference (or “recommend”), peptide sequence and handle, linker preference (or “recommend”), plus quantity/purity targets.

More FAQ'sAll FAQ's

Contact & quote request

For the fastest quote, send your siRNA sequences (sense/antisense + modifications), peptide sequence/handle, preferred attachment site (or constraints), stable vs cleavable preference, and quantity/purity targets. We’ll recommend a practical route plus purification/QC aligned to your application.

Fastest path
Request a Quote Attachment sites

What happens next: We respond with feasibility notes, recommended site/chemistry options, a QC plan, and pricing.

Fast quote checklist
  • Sense/antisense sequences + any 2′ modifications
  • Attachment preference (or “recommend”)
  • Peptide sequence + desired handle (Cys, azide, DBCO, etc.)
  • Linker preference (or “recommend”) + cleavable vs stable
  • Quantity (mg) + purity target + intended use

Not sure which route is safest? Send sequences and constraints—we’ll propose a handle + linker plan that preserves RISC function.

Talk to a chemist Request a quote

Recommended reading

Representative references covering siRNA delivery, oligonucleotide conjugation chemistry, and cleavable linker design.

  • siRNA delivery and endosomal escape fundamentals
    Background on uptake, endosomal trapping, and delivery strategies.
  • Oligonucleotide conjugation chemistries
    Handles (thiol/amine/azide/DBCO) and operational considerations for RNA compatibility.
  • Cleavable linker strategies
    Reducible, enzymatic, and stimuli-responsive approaches for intracellular release.

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Why Choose Bio-Synthesis

Trusted by biotech leaders worldwide for over 40+ years of delivering high quality, fast and scalable synthetic biology solutions.

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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