Nanomedicine novel strategies: deciphering the EV-metabolic axis as a natural nanocarrier network in lung cancer progression and cachexia.

The systemic progression of lung cancer involves a complex interplay between local tumor microenvironment (TME) dynamics and host-level metabolic decline, culminating in cachexia. Extracellular vesicles (EVs), have emerged as critical mediators in this process. This review constructs a comprehensive model of the "EV-metabolic axis" in lung cancer, framing EVs as natural nanocarriers within a systemic communication network that orchestrates a dual pathological process. Locally, EVs remodel the TME to support tumor growth, metastasis, and therapeutic resistance by transferringdiverse metabolic cargoes. Systemically, they transmit catabolic signals to distant adipose and muscle tissues, driving the severe tissue wasting characteristic of cachexia. This integrated perspective reveals the EV-metabolic axis as a central, targetable node in lung cancer pathology. From a nanomedicine perspective, targeting EV biogenesis, cargo loading, or uptake offers a novel, multifaceted therapeutic strategy to simultaneously inhibit tumor growth and mitigate cachexia, heralding a paradigm shift in future lung cancer treatment Scheme 1. This schematic illustrates the tripartite "EV-Metabolic Axis" framework linking local tumor metabolism, systemic EV trafficking, and cachexia development in lung cancer. In the Local Metabolic Axis, primary tumors and stromal cells (CAFs, TAMs, BMSCs) secrete extracellular vesicles (EVs) that reprogram glucose, lipid, and amino acid metabolism via cargoes such as miRNAs, metabolic enzymes, and cytokines - promoting glycolysis, glutamine addiction, ferroptosis resistance, and epithelial-mesenchymal transition (EMT). In the Circulatory System EV Transport Axis, EVs (40-150 nm exosomes, 50-1000 nm ectosomes) traverse biological barriers via membrane fusion, receptor-mediated endocytosis, or ligand-receptor binding, acting as natural nano-carriers. In the Systemic Cachexia Axis, circulating EVs deliver catabolic signals (e.g., miR-21, IL-6, HSP70/90, TGF-β, PTHrP) to distant organs - triggering adipose tissue browning, lipolysis, myofibrillar atrophy, and mitochondrial dysfunction - culminating in cancer-associated cachexia. This integrated axis positions EVs as both biomarkers and therapeutic targets across the nano-bio interface.