Rational Design of Safer Inorganic Nanoparticles via Mechanistic Modeling-informed Machine Learning

The safety of inorganic nanoparticles (NPs) remains a critical challenge for their clinical translation. To address this, we developed a machine-learning (ML) framework that predicts NP toxicity both in vitro and in vivo, leveraging physicochemical properties and experimental conditions. A curated in vitro cytotoxicity dataset was used to train and validate binary classification models, with top-performing models undergoing explainability analysis to identify key determinants of toxicity and establish structure-toxicity relationships. External testing with diverse mesoporous silica NPs validated the framework's predictive accuracy for in vitro settings. To enable organ-specific toxicity predictions in vivo, we integrated a physiologically-based pharmacokinetic (PBPK) model into the ML pipeline to quantify NP exposure across organs. Retraining the ML models with PBPK-derived exposure metrics yielded robust predictions of organ-specific nanotoxicity, further validating the framework. This PBPK-informed ML approach can thus serve as a potential Novel Alternative Method (NAM) to streamline NP safety assessment, enabling the rational design of safer NPs and expediting their clinical translation.