Extracellular vesicles: emerging anti-cancer drugs and advanced functionalization platforms for cancer therapy.

Increasing evidences show that unmodified extracellular vesicles (EVs) derived from various cells can effectively inhibit the malignant progression of different types of tumors by delivering the bioactive molecules. Therefore, EVs are expected to be developed as emerging anticancer drugs. Meanwhile, unmodified EVs as an advanced and promising nanocarrier that is frequently used in targeted delivery therapeutic cargos and personalized reagents for the treatment and diagnosis of cancer. To improve the efficacy of EV-based treatments, researchers are trying to engineering EVs as an emerging nanomedicine translational therapy platform through biological, physical and chemical approaches, which can be broaden and altered to enhance their therapeutic capability. EVs loaded with therapeutic components such as tumor suppressor drugs, siRNAs, proteins, peptides, and conjugates exhibit significantly enhanced anti-tumor effects. Moreover, the design and preparation of tumor-targeted modified EVs greatly enhance the specificity and effectiveness of tumor therapy, and these strategies are expected to become novel ideas for tumor precision medicine. This review will focus on reviewing the latest research progress of functionalized EVs, clarifying the superior biological functions and powerful therapeutic potential of EVs, for researchers to explore new design concepts based on EVs and build next-generation nanomedicine therapeutic platforms. Abbreviations: EVs: extracellular vesicles; MSCs: mesenchymal stem cells; DCs: dendritic cells; EMT: epithelial-mesenchymal transition; Exos: exosomes; MVBs: multivesicular bodies; ILVs: intraluminal vesicles; ESCRT: endosomal sorting complex required for transport-dependent pathway; GTPases: rab guanosine triphosphatases; VPS33B: vacuolar protein sorting protein 33b; TSAP6: p53-regulated protein tumor suppressor-activated pathway 6; KIBRA: kidney and brain expressed protein; SIRT1: Sirtuin1; ESCs: embryonic stem cells; hBMMSCs: human bone marrow MSCs; hMMSCs: human menstrual MSCs; hucMSCs: human umbilical cord MSCs; TRA2B: transformer 2ß; ESM1: endothelial cell specific molecule 1; ADMSCs: adipose MSCs; MARCKS: myristoylated alanine-rich C-kinase substrate; NK cells: natural killer cells; GM-CSF: granulocyte-macrophage colony stimulating factor; aPD-1: anti-programmed death-1; AFP: a-fetoprotein; TAM: tumorassociated macrophages; FasL: fas/fas ligand; LFA-1: lymphocyte function-associated antigen; DNAM1: DNAX accessory molecule-1; PD-1: programmed cell death protein; TRAIL: tumor necrosis factor-related apoptosis-inducing ligand; OXA: oxaliplatin; PDAC: pancreatic ductal adenocarcinoma; ADCs: antibody-drug conjugates; EGFR: epidermal growth factor receptor; HER2: human epidermal growth factor receptor 2; ADCC: antibody-dependent cellular cytotoxicity; STING: stimulator of interferon genes; TLR2: toll-like receptor 2; CAR: chimeric antigen receptor; OMVs: outer membrane vesicles; Redd1: DNA damage response 1; AGAP2: ankyrin repeat and PH domain 2; TFF3: trefoil factor 3; CPPs: cell penetrating polypeptides; ASO: santisense oligonucleotides; Qts: quantum dots; GIONP: gold-iron oxide nanoparticles; MYCBP: c-MyC binding protein; hTERT: human telomerase reverse transcriptase; 5-FU: 5-fluorouracil; CPPO: bis [2, 4, 5-trichloro-6-(pentoxycarbonyl) phenyl] oxalate; Dox-EMCH: aldoxorubicin; FA: folic acid; c-Met: mesenchymal-epithelial transition factor; DMD: duchenne muscular dystrophy; PTEN: phosphatase and tensin homologue; circRNA: circular RNA; RVG: rabies virus glycoprotein; sFlt-1: soluble fms-like tyrosine kinase-1; Cur: curcumin; Tf: transferrin; MVs: matrix vesicles; BPQDs: BP quantum dots; NSCs: neural stem cells; FAP: fibroblast activation protein-a; mRNA: messenger RNA; siRNA: small interfering RNA; miRNA: microRNA; circRNA: circular RNA; EDC: 1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide; NHS: N-Hydroxysuccinimide; PTX: paclitaxel; MTX: methotrexate; DOX: doxorubicin; TPZ: tirapazamine; Cis: cisplatin; PTT: photothermal therapy; PDT: photodynamic therapy; ROS: reactive oxygen species. [ABSTRACT FROM AUTHOR]