Engineered Polymeric Nanoparticles Based on Arylated Polyethylenimine Enable Spleen-Selective mRNA Delivery

Area of Science:

• Biotechnology
• Materials Science
• Nanomedicine

Background:

• Nonviral vectors are promising for messenger RNA (mRNA) therapeutics but struggle with organ selectivity after systemic administration.
• Achieving targeted delivery of mRNA to specific organs remains a significant hurdle in developing effective mRNA-based therapies.
• Polymeric nanoparticles (PNPs) offer potential solutions for controlled drug delivery, but their organ-targeting capabilities need further optimization.

Purpose of the Study:

• To engineer novel hydrophobized polymeric nanoparticles (PNPs) for efficient and organ-selective mRNA delivery.
• To synthesize and characterize new hydrophobized polymers derived from arylated polyethylenimine (PEI).
• To investigate the structure-function relationship of these PNPs for tunable organ targeting in mRNA therapeutics.

Main Methods:

• Synthesized nine new hydrophobized polymers by grafting 2-phenylethyl acrylate (PA) onto PEI with varying molecular weights and feeding molar ratios.
• Evaluated the resulting PNPs for mRNA delivery efficiency and selectivity both in vitro and in vivo using mouse models.
• Selected optimal PNP candidates based on in vitro transfection screening for further systemic delivery studies.

Main Results:

• Three optimal PNP candidates (6PP3-PNP, 12PP6-PNP, and 24PP12-PNP) were identified for in vivo studies.
• Remarkably, 6PP3-PNP demonstrated preferential mRNA delivery to the spleen, unlike the liver tropism of 12PP6-PNP and 24PP12-PNP.
• All tested PNPs, particularly 6PP3-PNP, exhibited excellent biocompatibility in vitro and in vivo.

Conclusions:

• The study successfully engineered tunable hydrophobized PEI-based PNPs for organ-selective mRNA delivery.
• A structure-function relationship was elucidated, demonstrating how polymer modification influences mRNA targeting.
• These findings expand the potential of mRNA therapeutics, particularly for immunotherapy, by providing a strategy for targeted delivery.