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Nanoparticle Characterization

Nanoparticle Characterization | scientific illustration of lipid nanoparticles (LNPs) | Nano ImagingNanoparticle Characterization

Therapeutic nanoparticles used in drug formulation & development, vaccine design & development, and gene therapy delivery are complex, and vary in composition, shape and size. As structure can change under stress, characterization of nanoparticles’ physicochemical properties is required to understand how they interact with their environment and can provide insight into the potential safety and efficacy of the final formulation. Size, shape, lamellarity and morphology of nanoparticles affect drug incorporation, stability, and release, which in turn affect cell toxicity, targeting and therapeutic efficacy. In addition, the study of encapsulation efficiency (full/empty liposomes or capsids) when looking at gene or drug delivery systems is crucial, as the presence of many empty particles or impurities (or non-intact capsid for VLPs) affects immunogenic response.

Cryo-TEM provides important structural details on a per-particle basis that cannot be captured by other methods, quickly visualizing individual particles in the size range of ~5-500 nm.

Imagine what you can achieve if you can gain a more thorough understanding of physical structure earlier in development. NanoImaging Services makes this possible.

Expertly-Performed Cryo-TEM Provides the Whole Picture, Earlier

Expertly-Performed Cryo-TEM Provides the Whole Picture, Earlier

Cryo-TEM can unveil many aspects of a sample simultaneously, in a single image (for example size, drug encapsulation, shape, morphology, impurities, integrity, aggregation), all with a tiny amount of sample. This makes cryo-TEM a powerful orthogonal technique to complement your characterization toolkit. Where a sample contains multiple particle types, for example in vaccine drug products, cryo-TEM outperforms. Similarly, when a sample needs to be analyzed at a concentration similar to drug preparation for IV administration, cryo-TEM is the solution, as it can handle relatively low sample concentrations.

Cryo-TEM image of liposomal enclosed Doxorubicin.

Expertly-Performed Cryo-TEM Provides the Whole Picture, Earlier

Cryo-TEM can unveil many aspects of a sample simultaneously, in a single image (for example size, drug encapsulation, shape, morphology, impurities, integrity, aggregation), all with a tiny amount of sample. This makes cryo-TEM a powerful orthogonal technique to complement your characterization toolkit. Where a sample contains multiple particle types, for example in vaccine drug products, cryo-TEM outperforms. Similarly, when a sample needs to be analyzed at a concentration similar to drug preparation for IV administration, cryo-TEM is the solution, as it can handle relatively low sample concentrations.

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Cryo-TEM image of liposome characterization.

Access the power of cryo-TEM through NIS to get a more in-depth view earlier, fast-tracking your therapeutic development.

We provide quick, flexible and cost-effective access to the answers cryo-TEM can reveal. Partner with the original and most experienced team in cryo-TEM and access cutting edge instruments to help accelerate your projects.

Expertly-Performed Cryo-TEM Provides the Whole Picture, Earlier

Expertly-Performed Cryo-TEM Provides the Whole Picture, Earlier

Cryo-TEM can unveil many aspects of a sample simultaneously, in a single image (for example size, drug encapsulation, shape, morphology, impurities, integrity, aggregation), all with a tiny amount of sample. This makes cryo-TEM a powerful orthogonal technique to complement your characterization toolkit. Where a sample contains multiple particle types, for example in vaccine drug products, cryo-TEM outperforms. Similarly, when a sample needs to be analyzed at a concentration similar to drug preparation for IV administration, cryo-TEM is the solution, as it can handle relatively low sample concentrations.

Access the power of cryo-TEM through NIS to get a more in-depth view earlier, fast-tracking your therapeutic development.

We provide quick, flexible and cost-effective access to the answers cryo-TEM can reveal. Partner with the original and most experienced team in cryo-TEM and access cutting edge instruments to help accelerate your projects.

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Cryo-TEM image of liposome characterization.

Types of Nanoparticles We've Imaged

  • Liposomes
  • Iron nanoparticles
  • Lipid Nanoparticles (LNPs), with mRNA, RNA, DNA payloads
  • Exosomes
  • Micelles
  • Polymeric nanoparticles
    • Associated Adeno-Virus (AAV) Characterization
    • Hepatitis B Virus (HBV ) Characterization
    • Human Papillomavirus (HPV) Characterization
    • Lentivirus Characterization
    Virus-Like Particles (VLPs)
    • Albumin NPs (Abraxane)
    • SARS-CoV-2 subunit vaccine
    Protein (subunit) based nanoparticles
  • Viruses, attenuated and recombinant (BSL-2 & below)
  • Extracellular Vesicles
  • Nanotubes

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Frequently Asked Questions

Explore how our experts can help you.

NIS Molecule

Why choose cryo-EM over other analytical methods?

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Cryo-EM allows for the direct visualization of biological molecules at moderate-to-high resolution without the need for crystallization, making it a powerful tool for structural biology. Additionally, cryo-EM can be used to study proteins in their native state, without the need for modification or crystallization, which can introduce artifacts or alter the structure of the protein.

Why should I use cryo-EM instead of X-ray Crystallography or Nuclear Magnetic Resonance (NMR) spectroscopy?

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Cryo-EM has several advantages over these techniques, including the ability to capture heterogeneous or dynamic molecular states in drug targets that are difficult or impossible to crystallize, including large (>300kDa) structures, protein:protein or protein:nucleic acid complexes, and membrane proteins. Additionally, cryo-EM requires smaller sample amounts than X-ray crystallography and NMR, using as little as 0.5-1 mg of protein at 1 mg/mL to obtain a structure. This can be particularly important for reagents generated from mammalian cells or are otherwise difficult to obtain. Overall, cryo-EM can address roadblocks with difficult samples such as preferred orientation, flexibility, aggregation, and more. Learn more about overcoming the challenges of preferred orientation in our blog post here.

Can we obtain additional/new information from cryo-EM after other methods failed?

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Yes, cryo-EM can provide valuable information even after other methods have failed. Cryo-EM can visualize large and complex structures that are difficult to crystallize, and it can also capture dynamic states of proteins and macromolecular complexes that are not easily accessible through other methods. Additionally, cryo-EM can reveal conformational changes that occur in response to ligand binding or post-translational modifications, which may not be apparent from other techniques.

Is cryo-EM 3 Å resolution better than crystallography 3 Å?

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It is difficult to compare the resolution of cryo-EM and crystallography maps solely based on a resolution limit since cryo-EM is a direct imaging method and the maps are not “phased” as in crystallography. As a direct method, the resulting maps from a cryo-EM data collection appear to be a “better” resolution than the refined nominal resolution may indicate. For instance, cryo-EM can provide structures with sidechains and small molecule ligand poses unambiguously defined at a nominal resolution of 3.5 Å, whereas density generated from a crystallographic experiment at that resolution cannot.

What is the likelihood of success for my sample?

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Each sample is different and we recommend an initial consultation with our team to provide an accurate estimation for success. NIS will always be fully transparent in regard to samples that might need more optimization or if a project might not be suitable for cryo-EM.

What kind of samples do you have experience with?

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NIS has solved over 150 3D structures with cryo-EM, with 76% of protein structures solved at 3.5 Å or better resolution.

We have extensive experience with a wide range of samples for cryo-EM, including large (>300 kDa) and medium-sized (>100 kDa) proteins, with and without ligands of interest. We have also worked with proteins/nucleic acid complexes, multi-domain proteins, and multi-component complexes. We are experienced in handling challenging samples, including membrane proteins including  GPCRs and ion channels. Additionally, we have solved structures of complexes utilizing PROTACs and molecular glues, and have significant experience studying antibody:epitope interactions at moderate and high resolutions. Our team is dedicated to providing high-quality cryo-EM services to our clients and working with them to advance their research in diverse biological systems.

We are not sure if we can fully commit to a cryo-EM project. What are our options?

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At NIS, we understand that committing to a cryo-EM project can be a big decision. That's why we offer a Starter Pack service, which includes a negative stain test and an initial feasibility assessment to help you evaluate the suitability of your sample for cryo-EM. The feasibility assessment can provide valuable information on sample quality and the potential for obtaining high-resolution structures. This service can help you make an informed decision about whether to proceed with a full cryo-EM project and can provide a cost-effective way to explore the capabilities of cryo-EM for your research. Read our blog about a proof of concept study here.

Are there size requirements?

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Ideally, your sample is at least 100 kDa of ordered mass. While less than 100 kDa is still feasible, the difficulty, timelines, and cost of the project will likely increase.

What quantity of my sample is required?

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Cryo-EM has an advantage over other methods in that only a small quantity is required. 1 mg of your protein/complex at 1 - 5 mg/mL concentration is an appropriate starting target. Depending on your sample, we might ask for a higher concentration, however, this can be discussed with our technical team on a call.

Are all reagents and buffer conditions amenable to cryo-EM?

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Most reagents and buffer conditions are amenable to cryo-EM. Exceptions include DMSO >0.5% which may interfere with the vitrification process and cause crystal formation. Similarly, excessive glycerol or sucrose can increase sample viscosity and cause issues with particle alignment during data collection.

Do you do different concentration ranges, how does it work?

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If your project is feasible for cryo-EM, it may undergo several optimization steps where different concentrations/grid types will be tried. Protein concentration and buffer composition is a strong determinant of both ice thickness and particle distribution and is a primary variable tested during our feasibility assessment. Generally, soluble proteins are tested at 1-5 mg/mL concentration, while integral membrane proteins are better behaved at higher concentrations.

What is the wait time to start a project?

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There is usually a 2-week lead time or less to initiate a project. It is best to ship your sample to us as soon as possible after your sample submission meeting, as there are frequent changes to schedules and microscope time can become unexpectedly available.

What are the turnaround times?

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Turnaround times for structural biology projects are typically 4-8 weeks from sample to map, depending on the desired project goals. To obtain a more accurate timeline estimate, we recommend you set up an initial meeting with our team.

Do we prepare target proteins?

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At NIS, we specialize in providing high-quality cryo-EM services to our clients, and we do not offer protein preparation services. However, we recognize the importance of sample quality in obtaining high-resolution structures through cryo-EM, and we offer ‘gene-to-structure’ protein consultancy services to help our clients optimize their sample preparation and experimental design.

What is the timeline for protein production to structure?

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In our experience, protein production takes between 4-6 months at most structural biology CROs. From sample receipt to structure, the timeline is typically 4-8 weeks, depending on the difficulty of the project. To get a more accurate estimation of timelines, we recommend you set up a meeting with our experts.

What documentation does NIS handle?

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We support and value our clients IP confidentiality. Our in-house contracts team will work closely and efficiently with your legal team to execute all necessary contracts. A CDA/NDA usually takes about a week or less to complete, and an MSA usually takes about 2-3 weeks. We prefer to put a CDA/NDA in place before our introductory meeting so that the conversation we can discuss project specific details.

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