Extracellular vesicles (EVs) are naturally secreted vesicles that have attracted a large amount of interest in nanomedicine in recent years due to their innate biocompatibility, high stability, low immunogenicity, and important role in cell-to-cell communication during pathological processes. Their versatile nature holds great potential to improve the treatment of several diseases through their use as imaging biomarkers, therapeutic agents, and drug-delivery vehicles. However, the clinical translation of EV-based approaches requires a better understanding of their in vivo behavior. Several imaging technologies have been used for the non-invasive in vivo tracking of EVs, with a particular emphasis on nuclear imaging due to its high sensitivity, unlimited penetration depth and accurate quantification. In this article, we will review the biological function and inherent characteristics of EVs and provide an overview of molecular imaging modalities used for their in vivo monitoring, with a special focus on nuclear imaging. The advantages of radionuclide-based imaging modalities make them a promising tool to validate the use of EVs in the clinical setting, as they have the potential to characterize in vivo the pharmacokinetics and biological behavior of the vesicles. Furthermore, we will discuss the current methods available for radiolabeling EVs, such as covalent binding, encapsulation or intraluminal labeling and membrane radiolabeling, reporting the advantages and drawbacks of each radiolabeling approach.

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Lung metastases represent the most adverse clinical factor and rank as the leading cause of osteosarcoma‐related death. Nearly 80% of patients present lung micrometastasis at diagnosis not detected with current clinical tools. Herein, an exosome (EX)‐based imaging tool is developed for lung micrometastasis by positron emission tomography (PET) using osteosarcoma‐derived EXs as natural nanocarriers of the positron‐emitter copper‐64 (64Cu). Exosomes are isolated from metastatic osteosarcoma cells and functionalized with the macrocyclic chelator NODAGA for complexation with 64Cu. Surface functionalization has no effect on the physicochemical properties of EXs, or affinity for donor cells and endows them with favorable pharmacokinetics for in vivo studies. Whole‐body PET/magnetic resonance imaging (MRI) images in xenografted models show a specific accumulation of 64Cu‐NODAGA‐EXs in metastatic lesions as small as 2–3 mm or in a primary tumor, demonstrating the exquisite tropism of EXs for homotypic donor cells. The targetability for lung metastasis is also observed by optical imaging using indocyanine green (ICG)‐labeled EXs and D‐luciferin‐loaded EXs. These findings show that tumor‐derived EXs hold great potential as targeted imaging agents for the noninvasive detection of small lung metastasis by PET. This represents a step forward in the biomedical application of EXs in imaging diagnosis with increased translational potential.

Lung metastasis represents the leading cause of osteosarcoma-related death. Progress in preventing lung metastasis is pretty modest due to the inherent complexity of the metastatic process and the lack of suitable models. Herein, we provide mechanistic insights into how osteosarcoma systemically reprograms the lung microenvironment for metastatic outgrowth using metastatic mouse models and a multi-omics approach. We found that osteosarcoma-bearing mice or those preconditioned with cell-secretome harbour profound lung structural alteration with airways damage, inflammation, neutrophil infiltration, and remodelling of the extracellular matrix with deposition of fibronectin and collagen by stromal activated fibroblasts for tumour cell adhesion. These changes, supported by transcriptomic and histological data, promoted and accelerated the development of lung metastasis. Comparative proteome profiling of the cell secretome and mouse plasma identified a large number of proteins engaged in the extracellular-matrix organization, cell-matrix adhesion, neutrophil degranulation, and cytokine-mediated signalling, which were consistent with the observed lung microenvironmental changes. Moreover, we identified EFEMP1, a secreted extracellular matrix glycoprotein, as a potential risk factor for lung metastasis and a poor prognosis factor in osteosarcoma patients.