Poly(aspartic acid)-Based Polymeric Nanoparticle for Local and Systemic mRNA Delivery

Abstract

Recently, therapeutics based on mRNA (mRNA) have attracted significant interest for vaccines, cancer immunotherapy, and gene editing. However, the lack of biocompatible vehicles capable of delivering mRNA to the target tissue and efficiently expressing the encoded proteins impedes the development of mRNA-based therapies for a variety of diseases. Herein, we report mRNA-loaded polymeric nanoparticles based on diethylenetriamine-substituted poly­(aspartic acid) that induce protein expression in the lungs and muscles following intravenous and intramuscular injections, respectively. Animal studies revealed that the amount of polyethylene glycol (PEG) on the nanoparticle surface affects the translation of the delivered mRNA into the encoded protein in the target tissue. After systemic administration, only mRNA-loaded nanoparticles modified with PEG at a molar ratio of 1:1 (PEG/polymer) induce protein expression in the lungs. In contrast, protein expression was detected only following intramuscular injection of mRNA-loaded nanoparticles with a PEG/polymer ratio of 10:1. These findings suggest that the PEG density on the surface of poly­(aspartic acid)-based nanoparticles should be optimized for different delivery routes depending on the purpose of the mRNA treatment.

Virus-like structures for combination antigen protein mRNA vaccination

“…Our work indicated that VLSs were capable of not only transfecting 293 encoding GFP or the S1 protein, was expressed dynamically in local tissue (Supplementary Fig. 4), similar to what has been reported for mRNA vaccines 20 . Interestingly, the rate of S1 antigen colocalization with DCs or macrophages in local tissue in mice in the VLS group was greater than that in mice in the mRNA-or protein-alone groups (Fig.…”

Recent Progress in Nucleic Acid Pulmonary Delivery toward Overcoming Physiological Barriers and Improving Transfection Efficiency

“…Intravenous injection of PEGylated poly(aspartic acid) could achieve pulmonary targeted mRNA transfection with increased cell viability compared to non‐PEGylated nanoparticles. [ 82 ] This PEGylated poly(aspartic acid) nanoparticle could be a potential lung‐targeted therapy for the local disease.…”

mRNA nanodelivery systems: targeting strategies and administration routes

“…Yum et al [ 175 ] synthesized PASP (DET/CHE) with a cyclohexyl ethyl (CHE) group, which caused significant mRNA expression in the lungs and even demonstrated mRNA transfection efficiency nearly 10 times higher than lipid materials commonly used on the market. Park et al [ 176 ] found that PEG-modified PASP (DET) (with a PEG/polymer ratio of 1:1) can induce mRNA expression in the lungs, but caution should be exercised as high PEG content may decrease the efficiency of mRNA delivery after intravenous injection. mRNA transduction and translation in the lungs were completely absent when the PEG/polymer ratio was 10:1.…”