GenShin: Guiding Rational Liposome Design by Ranking Liposomal Protein Corona through a Docking-Pose-Free GNN

Abstract

Rational design of lipid nanoparticles (LNPs) for tissue-specific delivery critically depends on predicting the composition of the protein corona that forms on the lipid surface after intravenous administration. However, conventional characterization of the protein corona relies on costly and time-consuming mass spectrometry experiments, which require physically prepared liposome samples and therefore cannot serve as a pre-synthesis screening strategy for large candidate lipid spaces. The adsorption of plasma proteins onto liposomal surfaces is shaped by lipid chemical structures, protein properties and the biological environment, making this process difficult to simulate directly. In this work, we propose that scoring lipid-plasma protein pairs and ranking the resulting scores can provide a practical signal for revealing the relative composition of the liposomal surface protein corona.Here we introduce GenShin, a geometry-enhanced pose-free graph neural network designed to score lipid-plasma protein pairs. GenShin is pretrained on compound-protein affinity data to initialize a generalizable scoring function and is then fine-tuned on a rank fine-tuning dataset constructed from liposomal protein-corona abundance measurements to adapt the model to lipid-plasma protein pair scoring. Before fine-tuning, GenShin achieves competitive pose-free affinity prediction on the PDBbind v2016 benchmark compared with representative pose-dependent models. CASF-2016 perturbation experiments using the pretrained GenShin model further show that pose-dependent inference substantially degrades when intermolecular poses are unreliable, whereas GenShin remains stable without requiring such poses. This supports the practical advantage of GenShin for large-scale lipid-protein scoring.