DADA-EV: domain-adaptive diffusion autoencoder for estimating tissue- and cell-type-specific origin in extracellular vesicle transcriptomes.

Tracing the tissue and cell-type origins of extracellular vesicles (EVs) in blood is critical for liquid biopsy and precision medicine, yet existing deconvolution methods remain limited by the need for labor-intensive reference signatures and poor adaptability to distribution shifts between tissue/cell-type datasets and EV transcriptomes. We introduce DADA-EV (Domain-Adaptive Diffusion Autoencoder for EVs), a hybrid deep learning framework that combines an autoencoder backbone with a generative simulation module and adversarial domain adaptation. DADA-EV features three key innovations: (1) a reference-free design that eliminates reliance on predefined signatures; (2) cross-domain generalization by aligning feature distributions between source (tissue/cell-type) and target (EV) domain; and (3) reduced dependence on source data during target-domain training. Extensive evaluations on pseudo-EV data show that DADA-EV consistently outperforms existing approaches, yielding accurate fraction estimates across diverse tissues and gene sets. Validation using in vitro cell-line mixtures further confirms its reliability in resolving complex compositions, demonstrating high sensitivity in detecting low-abundance targets. Applied to real EV transcriptomes, it reveals tissue- and cell-type heterogeneity across patient groups. In summary, DADA-EV provides a robust, reference-free, and generalizable solution for EV origin tracing, with strong potential to advance diagnosis, prognosis, and treatment monitoring via liquid biopsy.