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.