Recent advances in stimulus-assisted nanoprecipitation for nanoparticle synthesis

TL;DR

The paper addresses how external stimuli beyond simple mixing can decouple nucleation and growth in nanoprecipitation to achieve precise NP control. It surveys six stimulus classes (ultrasonic, electrical, supergravity, thermal, chemical, and multi-stimulus) across various mixing technologies, detailing mechanistic effects on local supersaturation and interfacial dynamics. Key contributions include mechanistic insights, representative examples, and guidance on continuous reactor design and data-driven optimization for advanced nanomaterial synthesis. The work highlights the potential to tailor NP properties for drug delivery, catalysis, and materials science, while identifying challenges in scalability, energy use, and mechanistic integration.

Abstract

Nanoprecipitation, the rapid solvent-displacement route to nanoscale phase separation, has matured from a simple batch operation into a versatile platform for nanomaterial synthesis. This review synthesizes recent progress in stimulus-assisted nanoprecipitation, wherein externally applied triggers (ultrasonic, electrical, supergravity, thermal, chemical, and photonic/other stimuli) are integrated with contemporary mixing technologies (batch, flash, microfluidic, membrane and high-shear reactors) to decouple and selectively control over nucleation, growth kinetics, and assembly processes. These methods allow for the precise tuning of the size, morphology, stability and functionality of nanoparticles (NPs), thereby broadening their applications in drug delivery, catalysis and materials science. We distill mechanistic principles by which each stimulus alters local supersaturation, chain mobility, interfacial instabilities, or droplet/film microreactor dynamics, and compare advantages and limitations by surveying research works from recent years. We also explore the potential development trends of multiscale coupling models, design rules for stimulus-compatible continuous reactors, and adoption of data-driven optimization frameworks to expand the capabilities of nanoprecipitation for advanced nanomaterial design.

Figures (5)

• Figure 1: Typical mixing approaches for nanoprecipitation. (a) Conventional batch nanoprecipitation. Adapted from Ref. bovone2022solvent. (b) FNP methods. (b-1) A confined impingement jet mixer (CIJ); (b-2) a multi-inlet vortex mixer (MIVM). Adapted from Refs. misra2024flashqi2025synthesis. (c) Microfluidic nanoprecipitation. (c-1) Representative schematics for microfluidic mixing geometries; (c-2) schematic of multi-stage microfluidic assisted co-delivery platform for multi-agent facile synchronous encapsulation. Adapted from Refs. vandenberg2025learningli2025multistage. (d) Membrane nanoprecipitation. Adapted from Ref. piacentini2022membrane.
• Figure 2: Schematic illustration of different types of external stimuli for nanoprecipitation.
• Figure 3: (a) Microbubble-integrated sidewall wedge acoustic micromixer. The inset: fluorescent polystyrene particle behavior in the presence of an acoustic field. Adapted from Ref. rasouli2019ultra. (b) Tesla structure-integrated sidewall wedge acoustofluidic mixer. Adapted from Ref. bachman2020acoustofluidic. (c) Schematic of the liposome synthesis platform based on an solid mount resonator (SMR). Adapted from Ref. xu2024microfluidic. (d) Top panel: schematic and working mechanism of the acousto-inertial chip. Bottom panel: gas-liquid interface deformation of an oscillating bubble with acoustic excitation (left); fluorescent polystyrene particle tracing the microvortex streaming (right). Adapted from Ref. lu2024vortex. (e) Synthesis of CaP-enzyme nanocatalysts with a multi-inlet acoustofluidic mixer. Adapted from Ref. wu2025acoustofluidic.
• Figure 4: Electrical-assisted nanoprecipitation. (a) Schematic of the continuous electrohydrodynamic mixing nanoprecipitation apparatus. Adapted from Ref. lee2024semibatch. (b) Electrospraying technique. (b-1) Schematic representation of the electrospray nanoprecipitation set-up; (b-2) Schematic illustration of different set-ups for electrospraying. Adapted from Refs. luo2015preparationrostamabadi2021electrospraying. (c) Schematic of the electrospray microfluidic chip and snapshots of the droplets generated under different voltages. Adapted from Ref. sun2016controlled. (d) Dielectrophoresis and electroosmotic flow principles. Adapted from Ref. wu2025design. (e) Schematic illustration of the micromixer for NP synthesis using AC electroosmosis, and the fluorescent images showing laminar streams of DI water/ethanol when the voltage is off and on. Adapted from Ref. modarres2020electrohydrodynamic. (f) Electric microfluidic devices. (f-1) AC electroosmosis micromixing on a lab-on-a-foil electric microfluidic device; (f-2) AC electrothermal wavy micromixer. Adapted from Refs. wu2022acmehta2023ac.
• Figure 5: (a) Supergravity-assisted nanoprecipitation using RPB. (a-1) synthesis device and schematic of the formation of ultrasmall MOFs in an ECRPB reactor. Adapted from Ref. chang2021general. (a-2) Schematic diagram of the synthetic route in an ICRPB reactor. Adapted from Ref. guo2023universal. (b) Thermal-assisted nanoprecipitation with two cases. (b-1) Schematic illustration of the preparation method of block copolymer NPs, and the STEM images of PSt-PI-30 NPs prepared at different temperatures; (b-2) Schematic of the all-aqueous nanoprecipitation process for formation of thermosensitive polymer prodrug NPs. Adapted from Refs. higuchi2010phaseguerassimoff2024thermosensitive. (c) Chemical-assisted nanoprecipitation with three cases. (c-1) The snapshot, TEM image, and schematic for the NPs produced by bad salt concentration (top) and good salt concentration (down); (c-2) Schematic illustration of the preparation of pectin NPs through continuous aqueous nanoprecipitation and the TEM image of pectin NPs; (c-3) Preparation of polymer NPs through nanoprecipitation using combinations of polymers bearing oppositely charged groups. Adapted from Refs. yang2023phaseding2023aqueouscombes2022protein.