Extracellular Vesicle-Mediated Strategies for Cancer Tissue Normalisation.

Tissue normalisation has emerged as an interesting therapeutic concept in oncology, aiming to correct the structural, metabolic, and immunological tissue abnormalities that enable tumour progression and treatment resistance. Rather than targeting cancer cells directly, this approach aims to re-establish homeostatic tissue architecture, immune surveillance, and metabolic balance. Interventions that target stromal components, such as cancer-associated fibroblasts (CAFs), immune cells, or stiffness of extracellular matrix (ECM), have been shown to shift tumour cells toward a less aggressive state, underscoring the plasticity of cancer cells and the importance of their interactions with the microenvironment. Extracellular vesicles (EVs) are increasingly recognised as both contributors to tissue dysfunction in tumours and promising tools for restoring tissue homeostasis. EVs circulate across most biofluids and can cross biological barriers to reach distant tissues. They naturally carry nucleic acids, including regulatory miRNAs, along with proteins, lipids, and metabolites that influence cell behaviour, making them attractive tools for tissue normalisation. Moreover, engineered EVs could be designed to deliver targeted "normalisation signals" and hold strong clinical potential as next-generation delivery systems. Here, we explore how EVs, whether native or engineered, can intervene in key tumour-driving processes, including senescence, fibrosis, inflammation, and immune evasion, to shift the microenvironment toward a normalised, less malignant state.