Science1 publisher2 min readPublished
Nature Methods comment argues solid-state nanopores could become key tools for studying supramolecular biochemistry beyond sequencing
The authors accept that de novo protein sequencing is worth chasing, and argue the field has crowded into it while size-tunable solid-state pores sit underused for measuring the assemblies that biology actually builds.
The Scientist · Science desk
What happened
- A comment published on nature.com under the title 'Solid-state nanopore sensing: the next workhorse of biophysical characterization' asks the nanopore community to redirect some of its effort.
- Its starting point is that DNA and RNA nanopore sequencing already runs on portable devices, and that the field's attention has since moved to de novo protein sequencing, where biological pores hold the lead.
- The authors argue that solid-state pores, tunable in size and easy to functionalize, are the better instrument for the macromolecular superstructures found in natural and synthetic biochemical systems.
- They accept sequencing as a worthy goal and press instead for nanopores aimed at supramolecular chemistry, naming drug screening, protein engineering and synthetic self-assembled systems as the openings.
- The abstract makes that case without reporting throughput, size resolution or error rates for any of the proposed applications.
Compiled by The ScientistSomething wrong?How this is made
Why it matters
- constraint A screening group evaluating this would need the numbers the abstract leaves out: how many particles per hour, how finely two assemblies can be told apart, and how often a pore calls a binding event that did not happen.
- decision The authors put the payoff after further gains in hardware, functionalization and experimental design, so a lab reading this is choosing to fund method development.
- capability The oligomer and protein-complex work already in the citation list is the part a biophysics lab could reproduce now. That capability is narrower than drug screening, and it is available.
- exposure The full argument costs $39.95 to buy, so the readers most likely to test it against their own instruments are the ones with institutional subscriptions.
The case rests on a property of the device. A solid-state pore is a hole in a thin synthetic membrane, and its diameter is set during fabrication, so the same platform can in principle be matched to an object far larger than a single polymer strand [3]. Biological pores are the ones positioned for reading an amino acid chain residue by residue [2]. The comment's argument is that the tunable aperture is the right tool for a different question: what a complex of many molecules looks like, one particle at a time [3].
That question has a real experimental literature behind it. That is what makes the piece more than advocacy. The reference list includes nanopore measurements of protein size, fluctuations and conformational changes [6], and label-free detection of single protein molecules and of protein-protein interactions in synthetic pores [7]. It also cites a 2025 Nature Reviews Chemistry review on detecting protein oligomers with nanopores [8]. Ligand binding has been read out too: DNA profiling to detect DNA-binding molecules [9], and analysis of individual RNA-antibiotic complexes [10]. For the drug-screening ambition [4], those two are the closest existing proof that a pore can see a small molecule bound to its target.
There is no reported throughput, no size resolution, no false-positive rate on a ligand series, and no comparison against the instruments a screening group already owns [1]. The authors frame the payoff as anticipated opportunities in drug screening, protein engineering and synthetic self-assembled systems [4]. That payoff is conditional on continuing improvements in hardware, functionalization and experimental design [5].
There is a practical asymmetry worth naming. Nanopore DNA sequencing reached the mainstream on portable, user-friendly devices [2]. A commercial platform is what turns a physics demonstration into a method a biologist uses routinely. Solid-state pores have no equivalent product line in the source material. A size-tunable pore is also a fabrication problem: every pore is slightly different.
I think the diagnosis is the stronger half of the argument. Crowding into one hard goal does leave adjacent measurements underexplored, and the cited oligomer and amyloid work [8][11] shows the adjacent measurements are tractable. The prescription is weaker, because screening and engineering both live or die on throughput and reproducibility, and those are exactly the quantities the abstract leaves unstated [1].
Nature charges $39.95 to buy the article, so the full argument sits behind a paywall for readers without institutional access [12].
What to watch
- A solid-state pore drug-screening result that reports a hit rate and a false-positive rate across a ligand series.
- Whether any commercial instrument ships solid-state pores with reproducible diameters. Reproducible diameters are what would make the comparison between two particles trustworthy.
- Whether protein-engineering groups start reporting assembly measurements from pores alongside the usual size-exclusion and microscopy data.