scACORN: Context-engineered agent orchestration of specialized small language models for single-cell transcriptomic interpretation

Abstract

Single-cell atlases now exceed 66 million cells, but turning a ranked expression profile and a free-form biological question into a reliable, evidence-grounded answer remains unsolved. Scaling a single model does not resolve this, because single-cell interpretation is a heterogeneous family of tasks whose correct answer depends on tissue, cohort, perturbation and annotation resolution. Here we present scACORN, an agentic alternative to monolithic single-cell language models that combines specialized small language models with context-engineered agent orchestration for their selection and composition at inference time. Each expert is built in two stages: domain-aligned contrastive adaptation fits a pretrained cell-to-text backbone to the transcriptomic geometry of a target dataset, and geometry-preserving specialization learns question-conditioned biological completions without eroding that geometry. A fixed orchestrating language model agent then selects and combines experts under a natural-language playbook that is itself optimized from textual feedback, with no gradient updates to the orchestrator. Across 10 Tabula Sapiens tissues, domain alignment raised transfer macro-F1 from 0.36 to 0.64 and Recall@5 from 0.87 to 0.97; specialized experts reached 0.89 mean exact-match annotation accuracy; and playbook optimization reduced unsupported gene citations from 14.5% to 3.5%. Our findings support specialization and orchestration as complementary responses to the heterogeneity and evidentiary demands of single-cell analysis.