Advances in Solid‑State Nanopore Fabrication and Applications

Background

Solid‑state nanopores are prized for their tunable pore size, robust mechanical stability, and compatibility with micro‑electromechanical systems (MEMS). They have been employed in DNA sequencing, water purification, protein detection, nanoparticle separation, and nanogenerators. The quest for low‑cost, high‑throughput fabrication remains a priority.

Since Jiali Li’s pioneering 2001 work on silicon nitride nanopores via argon‑ion irradiation, the field has split into top‑down (focused ion beam, high‑energy electron beam) and bottom‑up (electron‑beam‑assisted deposition, atomic‑layer deposition) methods. Common substrates include silicon nitride, silicon oxide, graphene, and MoS₂, each offering distinct advantages in pore geometry and chemical resilience.

Nanopore diameters can be tuned from sub‑nanometer to several hundred nanometers. Fabrication on insulating films ensures stability in harsh chemical environments and high temperatures, yet the final performance is highly dependent on the chosen process.

Development Process

After Li’s seminal work, researchers refined high‑energy beam techniques to improve throughput and reduce cost. Gierak et al. demonstrated a 2.5‑nm pore in a 20‑nm SiC film using an advanced Ga⁺ FIB system, while helium‑ion lithography has achieved 1.3‑nm pores in Si₃N₄. Parallel efforts focused on conventional methods—carbon‑nanotube dicing, mask etching with anodic aluminum oxide (AAO) or nanospheres, and nanoimprint lithography—to enable batch production without expensive beam equipment.

Solid‑state nanopore manufacturing roadmap

Fabrication Technologies

Ion Track Etching Method

Ion‑track etching exploits the higher etch rate in ion‑irradiated tracks to create pores in polymers and oxides. For example, Zhang et al. produced 40‑nm silicon nitride pores using 81‑MeV Br⁺ ions. Recent work by Harrell et al. shrank 2‑nm pores through nanogold deposition, though the method suffers from limited porosity and requires expensive accelerators.

Mask Etching Method

Mask‑based approaches use AAO, nanospheres, or nanoimprint templates. AAO masks provide uniform pore spacing but are fragile and wasteful. Nanosphere masks, combined with reactive ion etching, yield triangular pores with high density, yet their size is constrained by sphere diameter. Nanoimprint lithography offers reusable templates and sub‑5‑nm resolution, but demands high‑precision patterning and can suffer from template wear.

Preparation of solid‑state nanopores by mask etching methods. (a) GaAs solid‑state nanopore [25], (b) silicon nanopore [33], and (c) aluminum nanopore with different shapes [34]

Chemical Solution Etching Method

Electrochemical etching in KOH or HF solutions can produce porous silicon and silicon nitride nanopores with precise control over pore size and location. Park et al. pioneered DNA‑sequencing‑compatible silicon pores by combining lithography, KOH etching, and feedback‑controlled breakthrough. Subsequent work by Pedone et al. used electron‑beam lithography and real‑time current monitoring to achieve sub‑10‑nm pores with minimal shape distortion.

Preparation of solid‑state nanopore by chemical solution etching. (a) Double‑walled silicon nanopore [38], (b) silicon nanopore [27], and (c) highly controllable silicon nanopore [28]

High‑Energy Particle Etching and Shrinkage Method

High‑energy beams (e.g., Ga⁺ FIB, TEM electron beams, helium ions) allow direct nanopore patterning, but raw beam‑driven diameters often exceed 10 nm. Shrinkage strategies—atomic‑layer deposition of alumina or titanium oxide, electron‑beam–induced migration—have successfully reduced pores to 2 nm or less. Helium‑ion lithography, for instance, achieved 1.3‑nm Si₃N₄ pores in a 30‑nm film, offering a balance between resolution and throughput.

High‑energy particle etching and modification methods for the fabrication of solid‑state nanopore. (a) ALD shrinkage, (b) self‑calibration of nanopore edge, and (c) helium ion etching nanopore

Electrochemically Confined Nanopore Method

Electrochemically confined nanopores (ECNPs) harness localized electrochemical reactions, optical enhancements, and mass transport control within asymmetric channels. ECNPs enable high‑resolution, time‑resolved studies of single‑cell electrochemistry and have potential for biosensing and energy harvesting.

Application

DNA Sequencing

Nanopore sequencing, first conceptualized by the Kasianowicz group in 1996, offers a polymerase‑free, high‑throughput alternative to Sanger sequencing. Solid‑state nanopores provide robust, tunable channels that mitigate the pause‑and‑reverse artefacts common to biological pores. Recent advances, such as fluorescence‑parallel detection via total internal reflection (TIR) and simultaneous ion‑current readouts, promise microsecond‑scale throughput and sub‑nanometer spatial resolution, though challenges remain in controlling translocation speed and improving signal‑to‑noise ratios.

Total internal reflection fluorescence (FTIR) parallel detection of DNA sequence [58]. a Schematic diagram. b Signal map of optical and ion current signals detected in the experiment

Protein Detection

Solid‑state nanopores have been used to probe protein conformations, dynamics, and interactions. Early work detected bovine serum albumin and β‑lactoglobulin, revealing electric‑field‑induced unfolding. Subsequent studies using FIB‑etched silicon nitride pores of 20 nm and 3 nm diameters demonstrated the ability to resolve folded versus unfolded states and to distinguish ubiquitin linkage types. High‑bandwidth amplifiers and ultrathin HfO₂ pores have extended these capabilities to enzymes and larger biomolecules, opening avenues for real‑time single‑molecule biosensing.

Energy Conversion

Nanopore‑based micro‑devices convert ambient mechanical, chemical, or salinity‑gradient energy into electricity with minimal noise and zero CO₂ emissions. For example, solid‑state nanopore channels have demonstrated nanogenerators, solar‑to‑electric converters, and salinity‑gradient power harvesters with power densities comparable to commercial cation‑exchange membranes. The inherent chemical durability, thermal stability, and tunable ionic selectivity of solid‑state nanopores make them ideal for scalable, low‑power energy conversion systems.

Conclusions

This review highlights the rapid evolution of solid‑state nanopore fabrication—from high‑energy beam lithography to chemical‑solution etching and electrochemical confinement—and underscores their transformative impact on DNA sequencing, protein analysis, and nanogenerators. Continued progress toward cost‑effective, high‑throughput manufacturing will broaden the adoption of solid‑state nanopores across biotechnology, diagnostics, and energy technologies.

Abbreviations

AAO:

Anodic aluminum oxide

ALD:

Atomic layer deposition

CCD:

Charge‑coupled device

CMOS:

Complementary metal‑oxide‑semiconductor

EDX:

Energy‑dispersive X‑ray spectroscopy

EELS:

Electron energy‑loss spectroscopy

FIB:

Focused ion beam

MaIE:

Maltose‑binding protein

MEMS:

Micro‑electromechanical system

RIE:

Reactive ion etching

TEM:

Transmission electron microscope