Formulations indistinguishable by DLS, NTA and encapsulation efficiency (EE) can still differ in particle structure — and whether that difference is decision-relevant for your product is the question this page is built to help you answer. It lays out what ATEM’s cryo-EM measures, how precisely, how each readout is interpreted, and the case-study data behind every claim — including where it’s strong and where it stops.
Cryo-EM images individual LNPs vitrified in their native formulation buffer — no dilution, no labels, no models. Every particle is segmented and measured, then classified by a validated machine-learning model and released by a scientist.
Per-particle diameter and the full distribution — not an intensity-weighted average. Area and perimeter are measured directly from the pixel mask; diameter is derived from area.
Every particle assigned to its structural class — Solid Core, Biphasic Split, or Biphasic Dense (Blebbed) — giving the true population composition behind the average.
Circularity relative to a perfect sphere, computed from measured area and perimeter. Cryo-EM is the only method that resolves this directly.
Reliability is established two ways: technical replicates (same sample, repeated) define the method’s own noise floor, and accuracy is benchmarked against expert human operators. The numbers below are why a shift in the data can be read as a real change, not measurement scatter.
Benchmarked against a trained human operator, on data unseen in training. Human-like agreement on morphology class.
Standard deviation on average particle diameter across 10 technical replicates (5,000 particles each). Sub-nanometer reproducibility.
A random-draw study shows statistics stabilize beyond ~2,000 particles — essential for resolving less-frequent morphology classes.
 Read how we validated the method
Across an independent 21-formulation DoE and an in-vivo potency study, a consistent structural signature tracked with better function — and, just as informatively, independent Fraunhofer studies showed where that signature does not hold. Here’s the short version of each finding, how we got there, and where to read the full analysis.
Encapsulation stays high below a size threshold; above it, variance rises and EE falls.
In an independent 21-formulation DoE, encapsulation was consistently high (>90%) and low-variance for smaller particles, up to an overall-size threshold of ~55 nm (≈53 nm on the solid-core population); above it, EE variance increased and average EE decreased. The threshold is product-specific — we report the shape of the relationship, not a universal optimal diameter.
More Solid Core, fewer blebbed particles cooccured with better function.
Between two mixing technologies with identical lipids and mRNA, the more homogeneous, Solid-Core-rich material (64% vs 31%) showed significantly higher EE. Both structure and function differed — but the link did not survive within-group validation, so this is a population-level association, not a proven within-type correlation.
Near-spherical particles encapsulate better; falling shape ratio is a warning.
Healthy reference material sits above 92% circularity. In the formulation DoE, lower shape ratios were associated with worse encapsulation, and shape ratio was among the strongest synthesis-controlled structural variables.
The findings rest on validated precision (96.3% classification accuracy, sub-1 nm reproducibility) and human-in-the-loop release. Stress responses are reproducible across replicates, and structural differences are read against the method’s own measured noise floor.
Our data suggests that a structure-function relationship exists. Evidence is based on a limited number of case studies, so we are continuing to investigate. We state this as our current conclusion: structure relates to function — the specific links vary from case to case – and the evidence is actively being extended. We don’t claim a specific, universal link, and whether blebbing helps or harms remains product-specific (see Stage 3).
Summarizing the structural signature, the supporting data, the interpretation rules, and how to read a morphology report.
Follow your program from candidate selection to commercial release. Each step shows how cryo-EM is used and what to watch; each links to an in-depth guide covering how it works, what samples to send, and the readouts that matter.
Once a structural reference standard exists, cryo-EM supports several decisions outside the linear development path — each a comparison against that standard.
Cryo-EM uniquely combines 3D structural resolution, throughput, and native-state analysis, addressing the most relevant limitations of traditional methods.
Quantify how a change of raw-material source shifts your product’s structure against the standard.
Track the rate of change of the morphological profile over time as a stability-indicating readout.
 Read how we validated the method
A number that moved isn’t a finding until it clears the method’s own noise floor. These rules sit behind every application above.
Significant if >1 nm diameter, >2% fraction, >0.2% shape ratio. Rare classes carry larger sampling error — demand a bigger effect before trusting a shift there.
Stability is read as how fast structure drifts under stress, not a single snapshot. Compare rates across candidates to rank robustness.
In stress data, rising blebbed fraction is a degradation signature. Synthesis-induced blebs may behave differently — so the good/bad call is product-specific.
A correlation that holds across pooled samples but vanishes within homogeneous subgroups is a process artifact, not a structure–function law. Always test the link within group before believing it.
A single, simple set of requirements covers most LNP studies. If cold-chain or cross-border logistics are a hurdle, ATEM can manage the shipment end-to-end so you can focus on the science.
Requirements may vary by study type. Our scientists confirm the exact specification for your samples before you ship.
Cold-chain handling, customs paperwork and courier coordination are often the slowest part of getting started. We take that off your plate.
We’ve outlined where structural data supports each decision across the LNP lifecycle. To discuss how it applies to your program and scope the right study, reach out to our team.
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