Formulation-Driven Control of mRNA Polyplex Physicochemical Properties Enables Spleen-Targeted Systemic Delivery

Area of Science:

• Biomaterials Science
• Nanotechnology
• Immunology

Background:

• Efficient and organ-selective delivery of messenger RNA (mRNA) therapeutics is crucial but challenging.
• Current delivery systems require extensive material design efforts.

Purpose of the Study:

• To develop a simple formulation-based strategy for controlling mRNA polyplex physicochemical properties and biodistribution.
• To investigate the impact of ionic environment modulation on mRNA delivery and immune response.

Main Methods:

• Formulation of mRNA polyplexes using an amphiphilic polyaspartamide derivative (PAsp(DET/CHE)).
• Systematic modulation of polyplexes' N/P ratio and incubation with physiological saline (150 mM NaCl).
• Assessment of polyplex physicochemical properties, in vivo biodistribution, and antigen-specific immune responses (humoral and cellular) following ovalbumin (OVA) mRNA delivery.

Main Results:

• Polyplex size and surface potential influenced biodistribution after systemic administration.
• Incubation with NaCl induced controlled particle growth without mRNA release.
• NaCl-processed polyplexes shifted mRNA expression from lung to spleen, with accumulation in antigen-presenting cells.
• Robust antigen-specific humoral and cellular responses were observed after OVA mRNA delivery.

Conclusions:

• Fine-tuning the ionic environment offers a facile method to control mRNA polyplex assembly and in vivo distribution.
• This approach provides a scalable route to organ-selective mRNA delivery systems for vaccination and other applications.