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Device For Rapid, Tunable, And Scalable Generation Of Lipid Nanoparticle Formulations

Microfluidic device for generation of large, precisely-defined, diverse lipid nanoparticle libraries for screening LNP formulations.

Problem:

Lipid nanoparticles (LNPs) have broad applications such as delivery agents for gene editing cargo, immunotherapies, and many clinical applications. The structures of the lipid components of an LNP, their relative ratios, and complexing of these components with cargo are essential to LNP biological behavior. To conduct high-throughput formulation and screening of LNP formulations, there are over 1010 LNP design possibilities. While techniques from combinatorial chemistry and LNP barcoding enhance LNP design and screening strategies, there are no methods to controllably mix LNP components at a scalable throughput. Thus, there is a need for high-throughput technologies to systematically formulate and screen LNP formulations.

Solution:

The device conducts controlled mixing of nanoparticle components to produce large, precisely-defined, diverse libraries of LNPs by distributing multiple fluidic inputs across parallel microfluidic mixing devices. Components may be mixed at varying ratios to create unique nanoparticle formulations, where each fluidic input yields a different nanoparticle composition.

Technology:

The microfluidic device performs high-throughput synthesis of precise, distinct LNP formulations. A programmable pneumatic regulator enacts a fixed pressure on individual fluidic inputs, distributing them across resistors coupled to parallel microfluidic mixing units. This system allows for generation of defined, unique LNP formulations using identical mixing conditions in each generator. The device can be integrated with plate robotic automation for three-dimensional movement and collection of LNP outputs for further processing.

Advantages:

Device can produce 103 distinct LNP formulations per hour
The device is coupled to plate robotic automation for three-dimensional movement and LNP output collection for post-nucleation processing
The method supports synthesis of large LNP libraries for screening at a rate up to 1,000x faster than an individual using single microfluidic devices

Schematics of the microfluidic chip designed for synthesizing LNP libraries. (A) Diagram of six fluidic inputs with LNP components distributed across eight channels (Ch.1 to Ch.8). Flow rates are regulated by programmable pneumatic pressurizers and resistors. (B) Illustration of staggered herringbone mixers producing eight unique LNP formulations (F1 to F8) with precisely controlled compositions and fluid ratios.