Fine tuning of the net charge alternation of polyzwitterion surfaced lipid nanoparticles to enhance cellular uptake and membrane fusion potential

Keitaro Homma; Yutaka Miura; Motoaki Kobayashi; Wanphiwat Chintrakulchai; Masahiro Toyoda; Koichi Ogi; Junya Michinishi; Tomoyuki Ohtake; Yuto Honda; Takahiro Nomoto; Hiroyasu Takemoto; Nobuhiro Nishiyama

doi:10.1080/14686996.2024.2338785

Fine tuning of the net charge alternation of polyzwitterion surfaced lipid nanoparticles to enhance cellular uptake and membrane fusion potential

Sci Technol Adv Mater. 2024 Apr 10;25(1):2338785. doi: 10.1080/14686996.2024.2338785. eCollection 2024.

Authors

Keitaro Homma^{1

2}, Yutaka Miura^{1

2}, Motoaki Kobayashi^{1

2}, Wanphiwat Chintrakulchai^{1

2}, Masahiro Toyoda^{1

2}, Koichi Ogi³, Junya Michinishi³, Tomoyuki Ohtake³, Yuto Honda^{1

2

4}, Takahiro Nomoto^{1

5}, Hiroyasu Takemoto^{1

2

6}, Nobuhiro Nishiyama^{1

2

4}

Affiliations

¹ Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, Kanagawa, Japan.
² Department of Life Science and Technology, School of Life Science and Technology, Tokyo Institute of Technology, Kanagawa, Japan.
³ I&S Department, Corporate R&D division, NOF CORPORATION, Kanagawa, Japan.
⁴ Innovation Center of Nanomedicine (iCONM), Kawasaki Institute of Industrial Promotion, Kanagawa, Japan.
⁵ Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, Japan.
⁶ Medical Chemistry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Abstract

Lipid nanoparticles (LNPs) coated with functional and biocompatible polymers have been widely used as carriers to deliver oligonucleotide and messenger RNA therapeutics to treat diseases. Poly(ethylene glycol) (PEG) is a representative material used for the surface coating, but the PEG surface-coated LNPs often have reduced cellular uptake efficiency and pharmacological activity. Here, we demonstrate the effect of pH-responsive ethylenediamine-based polycarboxybetaines with different molecular weights as an alternative structural component to PEG for the coating of LNPs. We found that appropriate tuning of the molecular weight around polycarboxybetaine-modified LNP, which incorporated small interfering RNA, could enhance the cellular uptake and membrane fusion potential in cancerous pH condition, thereby facilitating the gene silencing effect. This study demonstrates the importance of the design and molecular length of polymers on the LNP surface to provide effective drug delivery to cancer cells.

Keywords: Lipid nanoparticles; membrane fusion; pH-responsiveness; polycarboxybetaine; siRNA.

Plain language summary

The study presents the unique characteristics of small interfering RNA (siRNA)-loaded lipid nanoparticles (LNPs) with different lengths of PGlu(DET-Car), revealing the length of PGlu(DET-Car) critically affects the formation of a stable LNP, the cellular uptake, membrane fusion, and gene silencing abilities.

Grants and funding

This research was supported financially by the Japan Science and Technology Agency (JST) through the open innovation platform for industry-academia co-creation (COI-NEXT) Program [Grant Number JPMJPF2202], Science and Technology Platform Program for Advanced Biological Medicine [JP21am0401018] from Japan Agency for Medical Research and Development (AMED), the Research on Development of New Drugs [23ak0101173] from AMED, JSPS KAKENHI [18H04163, N.N., 22H00581, N.N., 21K18322, Y.M.], and Five-star Alliance from the Ministry of Education, Culture, Sports, Science and Technology (MEXT). We thank Materials Analysis Suzukake-dai, Technical Department, Tokyo Institute of Technology.