Flexible nanoparticle development: process optimization & scale-up of a wide range of synthetic nanomedicines with Sunshine

Importance of the topic

Nanomedicine has emerged as a transformative approach in drug delivery, offering enhanced solubility, stability, bioavailability, and controlled release of therapeutic agents. Conventional batch methods for nanoparticle synthesis often suffer from poor reproducibility, wide size distributions, and labor‐intensive protocols. Automated microfluidic platforms, such as Sunshine by Unchained Labs, address these challenges by combining precise flow control with hydrodynamic flow focusing to generate highly uniform nanoparticles across scales.

Objectives and study overview

This application note demonstrates the flexibility of Sunshine to optimize and scale up the synthesis of diverse nanomedicine formulations, including PLGA polymer nanoparticles, phospholipid liposomes, and ionizable or cationic lipid nanoparticles (LNPs) for mRNA and RNA analogues. Key goals include:

• Establish robust protocols for milliliter‐scale screening of flow rate ratio (FRR), total flow rate (TFR), and in‐line dilution
• Achieve monodisperse particles (PDI < 0.2) with tunable average diameters between 20 nm and 150 nm
• Demonstrate continuous, multi‐liter production capability for preclinical studies

Methodology and instrumentation used

All nanoparticle types were produced via hydrodynamic flow focusing in microfluidic chips integrated with Sunshine automation. Key parameters included:

• Flow rate ratio (aqueous:organic ± dilution) varied to modulate mixing time and particle size
• Total flow rate adjusted to control Reynolds number and diffusion length scales
• Optional in‐line dilution modules to quench self‐assembly and adjust solvent composition

Instrumentation used:

• Sunshine microfluidic platform with Sunny 100 XT, 190 XT, 275 XT, and 490 Trident T chip modules
• Sunny Suite software for automated batch execution and protocol design
• Dynamic light scattering (DLS) for particle size distribution and PDI measurement
• Quant‐iT RiboGreen assay for mRNA encapsulation efficiency

Main results and discussion

PLGA nanoparticles: By varying the aqueous:organic FRR from 1:1 to 8:1 at a constant TFR of 3 mL/min, particle size decreased reproducibly from 83 nm to 57 nm with PDI below 0.1. Liposomes (phospholipon 90G/DDAB): FRR screening (1:0.5:1 to 1:3.5:1) yielded sizes of 20–150 nm; an FRR of 1:2:1 produced ~80 nm liposomes with PDI < 0.2. DMPC:cholesterol:DSPE‐PEG2000 liposomes: Increasing TFR from 2 to 5 mL/min at fixed FRR (3:1:1) reduced diameter by ~18% and improved PDI. mRNA‐LNPs (SM‐102/DSPC/cholesterol/DMG‐PEG2000): Over FRR range 2:1 to 6:1 at TFR 5 mL/min, LNP size declined from 68 nm to 58 nm and encapsulation efficiency exceeded 90%, peaking at 96%. Poly(A) RNA‐LNPs (DOTAP‐based): TFR variation (5–12 mL/min) at FRR 3:1 yielded sizes of 66–128 nm with PDI ~0.13 and RSD < 4%.

Benefits and practical applications

• High reproducibility and tight size control enable predictable pharmacokinetics and biodistribution
• Rapid screening of formulation parameters accelerates lead identification and process optimization
• Scalable continuous manufacturing supports preclinical and early clinical material needs
• Compatibility with a broad range of nanoparticle chemistries facilitates flexible platform development

Future trends and possibilities

Integration of real‐time monitoring and advanced process analytical technologies could further enhance quality by enabling in‐line size measurement and feedback control. Expansion to more complex feedstocks (e.g., biomolecules, stimuli‐responsive materials) and multistep on‐chip reactions will broaden the scope of nanomedicine discovery. Adoption of machine learning models trained on microfluidic process data may guide automated optimization and scale‐out strategies.

Conclusion

Sunshine’s automated microfluidic approach delivers a unified solution for rapid development, optimization, and scale‐up of synthetic nanomedicines. By precisely tuning FRR, TFR, and dilution parameters, it generates monodisperse nanoparticles across a variety of chemistries with high encapsulation efficiency. This platform accelerates drug delivery innovation and addresses manufacturing challenges in nanomedicine development.

References

1. Jiang et al. Overcoming ocular barriers with PLGA nanoparticles, International Journal of Nanomedicine, 2022. doi:10.2147/IJN.S272750