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

Organ-selective mRNA transfection enables precise regulation of gene expression in specific tissues and represents a pivotal strategy for advancing mRNA therapeutics toward multiorgan and multi-indication applications. However, prevailing delivery systems rely on tissue-specific ligands or polyplex chemical modifications, limiting the modularity, scalability, and clinical translatability of delivery systems. Herein, we report a mass-ratio-controlled organ-selective (MACO) mRNA delivery platform based on phosphatidyl polyethylenimine derivatives (PEI-PPs). Impressively, the MACO platform enables precise and reversible switching of mRNA transfection among the spleen (94%), liver (78%), and lung (95%) by simply adjusting the mass ratio of PEI-PP to mRNA, without requiring additional targeting ligands, charge modifiers, or chemical modifications. Mechanistic investigations revealed that varying mass ratios generate polyplexes with distinct surface charge and pK_a profiles, which in turn adsorb plasma protein coronas forming specific "protein fingerprints" that mediate organ-selective capability. The MACO mechanism represents the demonstration of organ-selective mRNA delivery governed solely by formulation parameters rather than polyplex structural alterations, providing a universal strategy to finely tune the mRNA multiorgan target.