Scientific Research Papers in which iLiNP was used

Development of the iLiNP Device: Fine Tuning the Lipid Nanoparticle Size within 10 nm for Drug Delivery.
ACS Omega 2018, 3, 5044−5051

This is the earliest paper on the development of iLiNP device.

The Use of a Microfluidic Device to Encapsulate a Poorly Water-Soluble Drug CoQ10 in Lipid Nanoparticles and an Attempt to Regulate Intracellular Trafficking to Reach Mitochondria.
J Pharm Sci. 2019 Aug;108(8):2668-2676
This paper describes the preparation of lipid nanoparticles encapsulating the water-insoluble drug coenzyme Q10 using the iLiNP device.

Development of a Microfluidic-Based Post-Treatment Process for Size-Controlled Lipid Nanoparticles and Application to siRNA Delivery.
ACS Appl. Mater. Interfaces. 2020 Jul 29;12(30):34011-34020
Lipid nanoparticle solutions prepared by the iLiNP device usually contain about 10-30% organic solvent, which, if left untreated, can induce changes in the membrane structure of the particles, resulting in re-fusion and aggregation of the particles and unintentionally increasing their particle size. By connecting a dilution microfluidic channel downstream of the iLiNP device to immediately reduce the organic solvent concentration, it was found that lipid nanoparticles with smaller diameter and sharper diameter distribution (=higher quality) can be prepared than before.

Lipid nanoparticles loaded with ribonucleoprotein–oligonucleotide complexes synthesized using a microfluidic device exhibit robust genome editing and hepatitis B virus inhibition.
J Control Release. 2021 Feb 10;330:61-71
This paper describes the successful preparation of protein-encapsulated lipid nanoparticles using the iLiNP device, which has been considered difficult. This was made possible by the excellent mixing (dilution) properties of the iLiNP device

One-Step Production Using a Microfluidic Device of Highly Biocompatible Size-Controlled Noncationic Exosome-like Nanoparticles for RNA Delivery.
ACS Appl. Bio Mater. 2021, 4, 1783−1793
RNA-encapsulated lipid particles have recently been used in vaccines against novel coronaviruses (mRNA vaccines). RNA, an anionic macromolecule, can be easily and commonly encapsulated in cationic lipid particles. However, cationic particles adsorb nonspecifically at various sites in the body, and there are concerns about the development of cytotoxicity at high doses, for example. On the other hand, anionic lipid particles such as exosomes and neutral lipid particles are expected to be relatively low-toxicity RNA carrier particles because of their low nonspecific adsorption. However, since anionic polymeric RNA does not have electrical attraction (electrostatic interaction) with anionic or neutral lipids, RNA could not be efficiently incorporated into the particles (low encapsulation efficiency). The achievement of this paper is the discovery that RNA can be encapsulated in anionic or neutral lipid particles at a high encapsulation rate by using the iLiNP device. Furthermore, we have succeeded in controlling the particle size to the size necessary for the particles to be taken up into the cell. In other words, the unique channel structure of the iLiNP device was found to be important for the production of low-toxicity RNA carrier particles.

Ultra-small lipid nanoparticles encapsulating sorafenib and midkine-siRNA selectively-eradicate sorafenib-resistant hepatocellular carcinoma in vivo.
J Control Release. 2021 Mar 10;331:335-349
In this paper, particle size optimization using the iLiNP device was carried out to maximize the effect of lipid nanoparticles.

Delivery of Oligonucleotides Using a Self-Degradable Lipid-Like Material.
Pharmaceutics. 2021 Apr 13;13(4):544.
The iLiNP device is used for the preparation of siRNA-encapsulated lipid nanoparticles containing the self-degradable lipid-like molecule ssPalmO-Phe as a component, which was jointly developed by the group of Professor Hidetaka Akita at Chiba University (currently at Tohoku University) and NOF Corporation.

Preparation of size-tunable sub-200 nm PLGA-based nanoparticles with a wide size range using a microfluidic platform.
PLoS One. 2022; 17(8): e0271050.
PLGA nanoparticles were prepared by the iLiNP device. The device can produce nanoparticles by just flowing raw material solution, and the particle size can be controlled by changing the pumping conditions. In this paper, for example, paclitaxel (PTX)-loaded nanoparticles were prepared and their anti-tumor effect was confirmed in vitro using HeLa cells. In this experiment, the smaller particle size of PTX-loaded nanoparticles (average 52 nm) showed a more rapid antitumor effect than the larger particle size (average 109 nm) or PTX alone.

Microfluidic Device-Enabled Mass Production of Lipid-Based Nanoparticles for Applications in Nanomedicine and Cosmetics.
ACS Appl. Nano Mater. 2022, 5, 6, 7867–7876
Lipid nanoparticles were prepared from highly concentrated lipid solutions using a 3-inlet type iLiNP device. Although the particle size of lipid nanoparticles usually increases when highly concentrated lipid solutions are used, the iLiNP device succeeded in increasing the concentration of nanoparticles (particles/mL) while suppressing the increase in particle size.
A common method to increase the production volume of lipid nanoparticles is to increase the volume of liquid pumped per unit time. However, this method requires larger equipment such as pumps, which increases costs, and requires concentration as a post-processing step. However, if a lipid nanoparticle suspension with a high nanoparticle concentration can be obtained using the iLiNP as described in this paper, these problems can be solved.

Microfluidic Platform Enabling Efficient On-Device Preparation of Lipid Nanoparticles for Formulation Screening.
ACS Appl. Eng. Mater. 2023, 1, 1, 278–286
The paper describes a “3-inlet type iLiNP device” that enables rapid and easy preparation of LNPs with various lipid ratios by arranging iLiNP structures in series. This enables the preparation of LNPs of various compositions more quickly than with commercially available 2- inlet type devices in the early stages of formulation studies.

Fine-tuning the encapsulation of a photosensitizer in nanoparticles reveals the relationship between internal structure and phototherapeutic effects.
J Biophotonics. 2023 Mar;16(3):e202200119.
The paper describes the development of MITO-Porter(rTPA), a lipid nanoparticle for mitochondrial delivery of rTPA. The iLiNP device was used for the preparation of MITO-Porter(rTPA). By using the iLiNP, LNP formulations (particle size: approx. 70 nm) with high rTPA content (approx. 80-100%) were succeeded.

Self-homing nanocarriers for mRNA delivery to the activated hepatic stellate cells in liver fibrosis.
J Control Release. 2023 Jan;353:685-698.
This paper describes the development of novel lipid nanoparticles (LNPs) for selective delivery of mRNA to activated hepatic stellate cells (aHSCs), which play an important role in the progression of liver fibrosis. The author, who has a unique lipid library, conducted LNP prototyping and optimization verification using the iLiNP device, and found promising new LNP compositions, including unique lipids. Further analysis of the mechanism of selective delivery revealed that C15A6, a type of lipid, has high affinity for aHSCs and that LNPs containing C15A6 are incorporated into aHSCs in a pKa (acid dissociation constant) dependent manner by clathrin-dependent endocytosis. Although ligands such as vitamin A have been considered necessary for selective delivery to hepatic stellate cells, this paper is considered groundbreaking in that it shows that LNPs without ligands can also be selectively delivered to hepatic stellate cells.

Controlling lamellarity and physicochemical properties of liposomes prepared using a microfluidic device.
Biomater Sci. 2023 Feb 8. doi: 10.1039/d2bm01703b. Online ahead of print.
Liposomal pharmaceuticals have been used in clinical practice for more than 20 years, and in recent years, continuous production has become possible using microfluidic devices. However, there have not been many cases in which the lamellar nature (layer structure) of liposomal lipid membranes has been analyzed in detail. In this paper, we investigated the relationship between the physical properties of liposomes and the preparation conditions of paclitaxel-encapsulated liposomes using the iLiNP microfluidic device. As a result, it was found that the number of lipid membranes changed by changing the initial lipid concentration and the flow rate ratio of the two raw material solutions, and it was confirmed that the release of the encapsulated paclitaxel was slower in liposomes with multiple membranes. One of the advantages of drug encapsulation in liposomes is the ability to provide sustained release, and this paper is very useful in that it shows that the sustained release profile can be easily adjusted using simple parameters such as the material concentration and flow rate ratio.

Mass production system for RNA-loaded lipid nanoparticles using piling up microfluidic devices.
Applied Materials Today 31 (2023) 101754
The iLiNP microfluidic device invented at Hokkaido University has been used by many users in Japan and overseas, mainly for the preparation of nanoparticle formulations on a laboratory scale. The rapid spread of mRNA vaccines (lipid nanoparticle formulations) has led to a rapid increase in demand for microfluidic devices that can mass produce nanoparticle formulations.
A research team from Hokkaido University and Shin-Etsu Chemical Co., Ltd. have developed a new iLiNP microfluidic chip for the mass production of nanoparticle drugs that takes advantage of the strengths of both companies, and have published their findings in a paper. This research result is a significant achievement that will contribute to the expansion of capability in the development and production of nanoparticle formulations using iLiNP technology.

Lipid nanoparticle-based ribonucleoprotein delivery for in vivo genome editing.
J Control Release. 355 (2023) 406-416
This paper describes the encapsulation of Cas protein and guide RNA complex (gRNA-Cas9 complex (RNP)) into lipid nanoparticles (LNP) using iLiNPs. In this paper, high gene knockdown efficiency (70-80%) was achieved by optimizing the single-stranded oligonucleotides to be incorporated into the RNP together with gRNA.

A system that delivers an antioxidant to mitochondria for the treatment of drug-induced liver injury.
Scientific Reports volume 13, Article number: 6961 (2023)
This paper describes the creation of mitochondria-directed lipid nanoparticles (CoQ10-MITO-Porter) loaded with coenzyme Q10 and their therapeutic effect on liver injury caused by acetaminophen overdose (APAP liver injury). APAP liver injury is a type of mitochondria-related disease caused by increased oxidative stress, and administration of CoQ10, which has antioxidant properties, is expected to be effective in the prevention or treatment of APAP liver injury, but there has been no efficient method of delivering CoQ10 to mitochondria. In this paper, we employ a mitochondria-directed lipid nanoparticle composition (MITO-Porter) and control the particle size of MITO-Porter to approximately 50 nm using the iLiNP device to increase its translocation to hepatocytes, and furthermore, by loading CoQ10 into the MITO-Porter, we have demonstrated that CoQ10 can be delivered to mitochondria in a mouse model of APAP liver injury. The results suggest a therapeutic effect when administered to the APAP liver injury model mice.

Construction of the systemic anticancer immune environment in tumour-bearing humanized mouse by using liposome- encapsulated anti-programmed death ligand 1 antibody- conjugated progesterone.
Frontiers in Immunology (2023) 14:1173728.
This paper describes the successful systemic modulation of the cancer immune environment using liposomes loaded with progesterone (P4) and anti-PD-L1 antibodies.
P4 is a hormone, and previous studies have suggested that cancer cells and activated T cells die in the presence of high concentrations of P4, while naive T cells and quiescent memory T cells survive. Therefore, liposomes (average particle size 44 nm) containing a high concentration of P4 and anti-PD-L1 antibody on the surface were prepared using the iLiNP device and administered to mice carrying PD-L1-expressing cancer cells, and the expected effects such as tumor growth inhibition were observed.

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