Mass-Ratio-Controlled Organ-Selective Phosphatidyl Polymer Carrier for In Vivo Targeted mRNA Delivery

Area of Science:

• Biotechnology
• Molecular Biology
• Drug Delivery Systems

Background:

• Organ-selective mRNA transfection is crucial for advanced mRNA therapeutics targeting multiple organs and diseases.
• Current delivery systems often require complex tissue-specific ligands or chemical modifications, hindering scalability and clinical use.

Purpose of the Study:

• To develop a modular and scalable mRNA delivery platform for organ-selective transfection.
• To demonstrate precise control over mRNA delivery to different organs by adjusting formulation parameters.

Main Methods:

• Development of a mass-ratio-controlled organ-selective (MACO) mRNA delivery platform using phosphatidyl polyethylenimine derivatives (PEI-PPs).
• Investigation of organ selectivity by varying the mass ratio of PEI-PP to mRNA.
• Mechanistic studies on polyplex characteristics (surface charge, pKa) and protein corona formation.

Main Results:

• The MACO platform achieved high and reversible mRNA transfection efficiency in the spleen (94%), lung (95%), and liver (78%) solely by adjusting the PEI-PP to mRNA mass ratio.
• No additional targeting ligands or chemical modifications were needed for organ selectivity.
• Varying mass ratios resulted in distinct polyplex surface charges and pKa values, leading to specific protein adsorption ('protein fingerprints') that mediated organ targeting.

Conclusions:

• The MACO platform offers a universal strategy for organ-selective mRNA delivery, governed by formulation parameters rather than polyplex structural changes.
• This approach enhances the modularity, scalability, and clinical translatability of mRNA delivery systems for multiorgan applications.