A Machine Learning Benchmarking Framework for Lipid Nanoparticle Transfection Efficiency Prediction

Lipid nanoparticles (LNPs) are among the most clinically mature platforms for nucleic acid delivery, yet designing lipids that are both effective and biologically safe remains a major bottleneck. In practical screening, toxicity is a decision-level constraint: if a lipid is toxic, its efficiency prediction is clinically irrelevant. We propose LipoAgent, a safety-aware multi-agent LLM framework for lipid discovery. LipoAgent combines domain-specific finetuning with a conditional prediction objective that enforces toxicity as a prerequisite for efficiency prediction, and further improves reliability via multi-agent verification with lightweight human oversight when disagreement persists. Across multiple foundation models, LipoAgent achieves an average 32% relative improvement in mRNA transfection efficiency prediction compared with other reported models for lipid design. Wet-lab validation confirms that virtual screening rankings reliably translate to biological transfection outcomes. The code is publicly available at https://github.com/SAI-Lab-NYU/LipoAgent.git.

Lipid nanoparticles (LNPs) have transformed RNA medicine, yet their clinical utility remains constrained by predominant hepatic accumulation after systemic administration. Redirecting LNPs to extrahepatic tissues requires understanding of how lipid chemistry and formulation composition jointly govern in vivo biodistribution. Here, we develop an interpretable machine learning framework to predict hepatic versus extrahepatic LNP accumulation and identify molecular design rules for extrahepatic RNA delivery. A literature-derived dataset of 476 intravenous LNP formulations was curated from 81 studies, integrating formulation composition, lipid chemical structures, and IVIS-based biodistribution profiles. Standardized SMILES representations of ionizable lipids, helper lipids, sterols, PEGylated or polymer-conjugated lipids, additional lipids, and polymer repeat units were converted into RDKit Expert descriptors and combined with formulation-level variables to generate an 808-dimensional feature representation. Logistic regression, random forest, and XGBoost achieved ROC-AUC values of 0.839, 0.866, and 0.874, respectively. SHAP-based interpretation and consensus feature ranking revealed that ionizable-lipid descriptors dominate biodistribution prediction, while formulation composition, particularly ionizable lipid, sterol, and PEGylated/polymer-conjugated lipid fractions, contributes substantially. The top 20 consensus features retained nearly all predictive information in tree-based models. The most informative features implicated electrotopological surface properties, charge- and hydrophobicity-weighted surface areas, molecular topology, and amide/alkyl structural motifs as drivers of extrahepatic accumulation. This study establishes an interpretable, data-driven strategy for decoding LNP biodistribution and provides actionable design principles for engineering LNPs beyond the liver.

Graph-theoretic approaches offer simplicity, interpretability, and low computational cost for molecular property prediction. Among these, the model proposed by Mukwembi and Nyabadza, based on the external activity $D(G)$ and internal activity $ζ(G)$ indices, achieved strong results on a small flavonoid dataset. However, its ability to generalize to larger and chemically diverse datasets has not been tested. This study evaluates the baseline $D(G)$-$ζ(G)$ polynomial model on five benchmark datasets from MoleculeNet, covering biological activity (BACE, 1,513 molecules), lipophilicity (LogP synthetic, 14,610 molecules; LogP experimental, 753 molecules), aqueous solubility (ESOL, 1,128 molecules), and hydration free energy (SAMPL, 642 molecules). The baseline model achieves an average $R^2 = 0.24$, confirming limited transferability. To address this, a systematic enhancement framework is proposed, progressively incorporating Ridge regularization, additional graph descriptors, physicochemical properties, ensemble learning with Gradient Boosting, Lasso feature selection, and a hybrid approach combining topological indices with Morgan fingerprints. The enhanced models raise the average best $R^2$ to 0.79, with individual improvements ranging from 165% to 274%. All improvements are statistically significant ($p < 0.001$). A direct comparison with a Graph Convolutional Network under identical experimental conditions shows that the enhanced classical models match or outperform deep learning on all five datasets. Comparison with the recent GNN+PGM hybrid of Djagba et al.\ further confirms competitiveness, with the enhanced models achieving the best results on two datasets and tying on one. The entire framework requires no GPU, trains in under five minutes, and uses only open-source tools, making it accessible for researchers in resource-limited settings.