Exosomes (30–150 nm), as a type of small extracellular vesicles, have been shown to be widely present in a variety of body fluids (e.g., blood, urine, and saliva) [1]. Exosomes are rich in biological information, including metabolites, proteins, and nucleic acids [2], and have become another very promising source of diagnostic markers for disease beyond circulating tumor cells (CTCs) and cell-free DNA (cfDNA) [3,4]. However, the separation efficiency, yield and quality of exosomes still can not meet the requirement for disease diagnosis by exosomal biomarkers. At present, as the gold standard for exosome isolation, ultracentrifugation (UC) is one of the most commonly used methods [5]. However, it is not suitable for exosome-based liquid biopsy, due to the long time-consuming, high sample consumption and expensive cost for specialized instruments. Compared with UC, precipitation with polymers has the characteristics of simplicity and speed, and the separation process does not require special equipment and professional operators [6]. Unfortunately, residual precipitants (e.g. PEG) in the sample are not compatible with the subsequent analysis especially when using mass spectrometry [7]. In addition, several other common exosome isolation methods including size-exclusion chromatography, antibody-based isolation methods, etc. also have disadvantages such as low efficiency and high price in exosome isolation [8], [9], [10]. Therefore, there is an urgent need to develop a rapid and efficient method for exosome isolation, especially for plasma with complex composition.

In recent years, materials with different functionalities have been developed with low sample consumption, simple and fast enrichment process, for enrichment of exosomes [11], [12], [13], [14], [15], [16], [17], [18]. For example, Qian et al. [11] used titanium dioxide (TiO2) to isolate exosomes from human serum based on specific interactions between phospholipid bilayers and TiO2 for protein biomarker discovery of pancreatic cancer. Metal-organic frameworks (MOFs) have also been used for exosome isolation due to their unique high specific surface area and good stability. Qiao et al. [12] developed Tim4@ILI-01 immunoaffinity sheet to isolate exosomes from serum from lung adenocarcinoma patients. To achieve fast and automatic isolation of exosomes, magnetic materials have been developed [13], [14], [15], [16]. Deng et al. constructed magnetic materials of aptamer- gold-decorated polycrystalline carbon (CoMPC@Au-Apt) for capturing urinary exosomes from early gastric cancer patients and healthy controls and subsequent exosome metabolic pattern analysis [14]. The characteristics of these representative exosome isolation materials are compared in the Table S1. It is worth noting that the magnetic properties of the material can provide fast and high throughput isolation of exosomes toward numerous clinical samples for biomarker discovery and liquid biopsy.

Due to the abundance of f-orbitals in rare earth elements [19], it has a strong adsorption effect on the phosphate groups. Based on this principle, various rare earth elements have been used for highly selective enrichment of phosphorylated peptides [20], [21], [22], [23]. Exosomal membranes are composed of amphiphilic phospholipids with hydrophobic tails and hydrophilic phosphate heads. We hypothesized that rare earth elements were also able to bind to the hydrophilic phosphate heads of lipids exposed on the outer surface of the lipid bilayer. In this study, a variety of rare earths were first explored for the interaction with phosphate compound and plasma exosome. Subsequently, in order to achieve rapid and convenient isolation of exosomes, the most efficient rare earth-based magnetic nanomaterials (Fe3O4@SiO2@Eu2O3) were synthesized and rapid and effective separation of exosomes from human plasma was achieved (Fig. 1). Notably, the developed material exhibited higher enrichment capacity, less time consumption and more convenient handling than UC. Moreover, the nanomaterials were used for the separation of exosomes from the plasmas of patients with hepatocellular carcinoma and healthy controls toward metabolomics study using high-resolution mass spectrometry. The results showed that 70 differentially expressed metabolites were identified, involving amino acid and lipid metabolic pathway. Collectively, the developed methods provided an alternative strategy for disease diagnosis or postoperative clinical monitoring.