The Importance of Poly(ethylene glycol) and Lipid Structure in Targeted Gene Delivery to Lymph Nodes by Lipid Nanoparticles

Abstract

Targeted delivery of nucleic acids to lymph nodes is critical for the development of effective vaccines and immunotherapies. However, it remains challenging to achieve selective lymph node delivery. Current gene delivery systems target mainly to the liver and typically exhibit off-target transfection at various tissues. Here we report novel lipid nanoparticles (LNPs) that can deliver plasmid DNA (pDNA) to a draining lymph node, thereby significantly enhancing transfection at this target organ, and substantially reducing gene expression at the intramuscular injection site (muscle). In particular, we discovered that LNPs stabilized by 3% Tween 20, a surfactant with a branched poly(ethylene glycol) (PEG) chain linking to a short lipid tail, achieved highly specific transfection at the lymph node. This was in contrast to conventional LNPs stabilized with a linear PEG chain and two saturated lipid tails (PEG-DSPE) that predominately transfected at the injection site (muscle). Interestingly, replacing Tween 20 with Tween 80, which has a longer unsaturated lipid tail, led to a much lower transfection efficiency. Our work demonstrates the importance of PEGylation in selective organ targeting of nanoparticles, provides new insights into the structure–property relationship of LNPs, and offers a novel, simple, and practical PEGylation technology to prepare the next generation of safe and effective vaccines against viruses or tumours.

Novel Surface-Modified Bilosomes as Functional and Biocompatible Nanocarriers of Hybrid Compounds

“…In our contribution, different types of structured phospholipid vesicles were used as drug delivery systems for potential anticancer therapy to achieve high therapeutic efficiency. Effective accumulation of these nanostructures in target tissues depends on their physicochemical properties such as particle size distribution and surface charge [ 31 ]. Thus, developing safe and stable nanoscopic carriers requires the preparation of monodisperse colloidal systems of a specific size.…”

Lipid-Based Nanoparticles in the Clinic and Clinical Trials: From Cancer Nanomedicine to COVID-19 Vaccines

“…Structurally, reports have shown that using a linear or branched PEG chain can significantly dictate the targeting behaviour and transfection ability of LNPs. Truong group synthesized three LNPs with either Tween 80 (2-[2-[3,5-bis(2-hydroxyethoxy)oxolan-2-yl]-2-(2-hydroxyethoxy)ethoxy]ethyl (E)-octadec-9-enoate), Tween 20 (2-[2-[3,4-bis(2-hydroxyethoxy)oxolan-2-yl]-2-(2-hydroxyethoxy)ethoxy]ethyl dodecanoate) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol) (DSPE-PEG) to encapsulate pDNA and investigate their targeting ability, stability and extent of transfection [ 52 ]. Tween 20 and Tween 80, both non-ionic surfactants are made of saturated carbon tails with similar branched PEG architecture, compared to the linear structure of DSPE-PEG ( Figure 4 ).…”

“…LNPs with the linear DSPE-PEG showed predominantly localized transfection at the injection site. Altogether, this study demonstrated that PEGylation of LNPs with branched PEG is a viable approach to target organs with effective transfection selectively [ 52 ]. It is hypothesized that, aside from the molecular weight and structure, the PEG density on the particle is also an important factor.…”

Nano-Enabled COVID-19 Vaccines: Meeting the Challenges of Durable Antibody Plus Cellular Immunity and Immune Escape

“… 38 , 47 These studies also assisted in dosimetry development and demonstrating that the intramuscular route of administration generates sufficient inflammatory effects to assist the recruitment of APCs and antigen presentation in regional lymph nodes. 21 , 116 , 117 …”