GEM-GPT Enables Personalized Cell Type-Resolved Therapeutic Design for Systems Pharmacology.

Generative AI is transforming drug discovery, yet most approaches follow one-drug-one-target paradigms ill-suited to the heterogeneity of chronic, systemic diseases. Systems pharmacology offers an alternative, but generative tools designed for it remain scarce. We introduce GEM-GPT, a transcriptomics-guided framework that generates personalized therapeutic candidate molecules intended to shift cell type-specific disease states toward healthy phenotypes. GEM-GPT uses a biology-inspired deep fusion architecture that couples a single-cell RNA-sequencing foundation model with a molecular GPT, modeling cell type-specific chemical-gene interactions throughout molecule generation rather than through fixed conditioning. Across bulk and single-cell chemical perturbations and CRISPR knock-out signatures, GEM-GPT outperforms state-of-the-art baselines, produces cell type-resolved molecules, and generalizes to unseen cellular contexts. In a case study on opioid use disorder (OUD), it generates novel candidates, recovers FDA-approved OUD-related drugs absent from training, and yields predicted binders to OUD-related targets. GEM-GPT bridges single-cell omics and molecular generation for personalized, cell-type-resolved, systems-aware therapeutic design.