"Exosomal blueprint of lung-tropic metastasis: molecular signatures, microenvironmental conditioning, and...

Exosomes are increasingly recognized as central regulators of organ-specific metastasis, and this review concentrates on their contribution to lung-directed dissemination. Yet, a detailed and integrative synthesis of how exosomes contribute to lung-directed metastatic spread-and what these mechanisms mean for clinical translation-remains largely absent from the current literature. Extracellular vesicles (EVs), particularly exosomes measuring 30-150 nm, are nanoscale, lipid bilayer-enclosed structures secreted by nearly all cell types. In cancer, tumor-derived exosomes act as potent mediators of intercellular signaling, enabling metastatic spread by modulating inflammation, angiogenesis, extracellular matrix dynamics, and immune evasion. Their molecular cargo, especially integrin profiles, plays a decisive role in determining metastatic tropism: integrins α6β4 and α6β1 are strongly associated with pulmonary colonization, while αvβ5 directs metastasis toward the liver. In malignancies such as breast, colorectal, melanoma, and pancreatic cancer, exosomal proteins and RNAs remodel the lung microenvironment, enhancing vascular permeability and attracting stromal and immune components that establish a receptive pre-metastatic niche. Clinically, exosomes are emerging as powerful liquid biopsy biomarkers and as promising platforms for targeted drug delivery. Advances in EV bioengineering now permit tailoring of surface molecules and cargo to improve pulmonary selectivity, for instance, supporting selective delivery of therapeutic payloads to pulmonary tumors or altering immune dynamics within the lung microenvironment, while omics-based and imaging technologies support detailed profiling and tracking. Early clinical trials of exosome-derived vaccines and therapeutic carriers have demonstrated feasibility and safety, although no EV-based therapy has yet achieved regulatory approval. This review integrates mechanistic insights, niche biology, and translational advances to highlight the unique role of exosomes in lung-specific metastasis and their potential as diagnostic and therapeutic tools in precision oncology.