A simple epoxide modification strategy to construct amino-functional poly(2-oxazoline) mRNA delivery vectors

Area of Science:

• Biomaterials Science
• Polymer Chemistry
• Gene Therapy
• Vaccinology

Background:

• Messenger RNA (mRNA) delivery vectors are crucial for vaccines and gene therapy.
• Polymer-based vectors offer tunable structures and biocompatibility but face efficiency challenges.
• Poly(2-oxazoline) (POx) is a promising biomaterial with limited exploration in mRNA delivery.

Purpose of the Study:

• To engineer poly[2-(5-aminopentyl)-2-oxazoline]-based (PAmOx) polymers as efficient mRNA delivery vectors.
• To investigate the impact of polymerization degree and grafted epoxide molecules on mRNA delivery efficiency.
• To evaluate the in vitro and in vivo performance of the novel PAmOx-based mRNA vectors.

Main Methods:

• One-step ring-opening reaction between PAmOx and epoxide molecules (1,2-epoxydecane) to create DP50-PE6.
• In vitro assessment of mRNA transfection efficiency.
• In vivo studies involving intramuscular and intravenous administration in mouse models.
• Tumor growth inhibition assay using DP50-PE6/mOVA complex with anti-PD1 therapy.

Main Results:

• DP50-PE6 demonstrated a 3.3 × 10^5-fold increase in mRNA transfection efficiency compared to parent PAmOx.
• In vivo intramuscular administration showed robust mRNA expression at the injection site for two days.
• Intravenous administration led to selective spleen targeting (85.1% of total expression).
• DP50-PE6/mOVA combined with anti-PD1 achieved over 90% tumor suppression in a melanoma model.

Conclusions:

• Engineered PAmOx polymers, specifically DP50-PE6, are highly efficient mRNA delivery vectors.
• These POx-based vectors exhibit promising in vivo biodistribution and therapeutic potential.
• The study highlights the significant potential of POx-based materials for advancing nucleic acid delivery technologies.