What if a short peptide on the surface of an LNP could determine which organ receives your mRNA? A new study, “Peptide codes for organ-selective mRNA delivery”, led by Huajian Gao and Yue Shao at Tsinghua University, introduces a modular POST (Peptide-encoded Organ-Selective Targeting) platform that uses DSPE-PEG-linked peptides to direct systemic LNPs to different extrahepatic organs.

Key Findings
• The POST peptide library reveals clear tropisms: for example, 6R targets the lung, 6D targets the spleen, and 3R targets the liver. A single amino acid change can switch organ preference or delivery efficiency.
• POST peptides influence the formation of distinct protein coronas on LNPs, and these sequence-dependent coronas are linked to selective uptake in different organs.
• The approach is versatile: POST works with multiple clinically relevant ionizable lipids (SM-102, ALC-0315, LP01), supports co-delivery of mRNA and ASOs, and has the potential to target organs such as the placenta, bone marrow, adipose tissue, and testis.

Why it matters
POST transforms LNP organ targeting into a modular, sequence-encoded surface code, surpassing crude charge-based strategies and enabling programmable tropism for precision RNA therapeutics. The approach is compatible with different LNP chemistries and amenable to AI-guided sequence design, which could accelerate rational development of organ-selective delivery vehicles.

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https://doi.org/10.1038/s41563-025-02331-6