Engineered exosomes-based theranostic strategy for tumor metastasis and recurrence

Abstract

Metastasis-associated processes are the predominant instigator of fatalities linked to cancer, wherein the pivotal role of circulating tumor cells lies in the resurgence of malignant growth. In recent epochs, exosomes, constituents of the extracellular vesicle cohort, have garnered attention within the field of tumor theranostics owing to their inherent attributes encompassing biocompatibility, modifiability, payload capacity, stability, and therapeutic suitability. Nonetheless, the rudimentary functionalities and limited efficacy of unmodified exosomes curtail their prospective utility. In an effort to surmount these shortcomings, intricate methodologies amalgamating nanotechnology with genetic manipulation, chemotherapy, immunotherapy, and optical intervention present themselves as enhanced avenues to surveil and intercede in tumor metastasis and relapse. This review delves into the manifold techniques currently employed to engineer exosomes, with a specific focus on elucidating the interplay between exosomes and the metastatic cascade, alongside the implementation of tailored exosomes in abating tumor metastasis and recurrence. This review not only advances comprehension of the evolving landscape within this domain but also steers the trajectory of forthcoming investigations.

Keywords: Biomimetic; Engineered exosome; Metastasis; Recurrence; Therapeutics; Tumor.

Graphical abstract

Fig. 1

The engineering strategies of exosomes can be divided into bottom-up, top-down and hybrid biomimetic strategies. (A) Bottom-up strategies are exosome or single molecule-based assembly into larger and more complex engineered exosomes, including genetic engineering, chemical modification, membrane editing techniques, and mechanical methods. (B) Top-down strategies gradually disassembles cells into vesicular structures with specific functions, including co-incubation, chemical blebbing, CNP, filtration, microfluidic technology, and membrane package. (C) The hybrid biomimetic strategy combines cell membrane proteins and liposomes of various cell types to design artificial chimeric exosomes (ACEs), which have the characteristics of tumor targeting and multifunctional customization.

Fig. 2

Typical ways of engineered exosomes to interfere with metastasis. (A) Loaded anti-cancer drugs and delivering them to distant tumors through the blood circulation. (B) Loaded with siRNA and delivered to tumor cells to interfere with the expression of mRNA related to metastasis genes. (C) Interference with TEXs-mediated communication between cancer cells and the formation of PMNs. (D) Activated the host immune system and suppressed the immunosuppressive response of the tumor, indirectly inhibiting metastasis.

Fig. 3

Engineered modification of metastasis-related TEXs with bio-orthogonal nanoparticles. (A) Bio-orthogonal nanoparticles targeting tumor and TEXs mechanism of action. (B) Construction and characterization of bio-orthogonal nanoparticles. (C) PMNs inhibition effect of bio-orthogonal nanoparticles on mice bearing orthotopic PDAC, among which AC4Manaz-DP +DBCO-GEM/ISO-DP had the strongest inhibitory effects on TGF-β expression, stectin activation, fibonectin deposition and bone marrow derived macrophages. (D) After bio-orthogonal nanoparticle treatment on mice bearing pancreatic cancer liver metastases, Bioluminescent images of mouse livers and H&E staining of livers. Reproduced with permission from . Copyright 2023 Wiley-VCH GmbH.

Fig. 4

Multi-combination application of engineered exosomes in metastasis therapy. Engineered exosomes constructed by nanobiology can enhance immune effects and deliver drug molecules to tumor cells, and interfere with tumor metastasis and recurrence through multiple pathways such as combined immunotherapy, gene therapy, chemotherapy, and optical therapy.

Fig. 5

Nanotechnology-based engineered exosomes intervene in metastasis with gene therapy. (A) Schematic illustration of engineered exosome-mediated siRNA delivery for inhibition of postoperative metastasis in breast cancer. (B) Synthesis and characterization of CBSA. (C) The highest fluorescence expression was observed in the lung after intravenous injection of CBSA/siS100A4@Exosome24h. (D) CBSA/siS100A4@Exosome was used in the postoperative lung metastasis model, and the mean number of pulmonary metastatic nodules was decreased by gross eyes. Reproduced with permission from . Copyright 2019 Elsevier B.V.

Fig. 6

EMPCs based on multiple mechanisms are used to inhibit tumor metastasis. (A) Schematic representation of the EMPCs with CTCs clearance, CuB-mediated metastasis suppression, ROS enhancement, and cascade amplified PTX chemotherapy. (B) EMPCs showed excellent in vitro CTCs capture efficiency and in vivo CTCs elimination efficiency. (C) In both MDA-MB-231 xenograft and orthotopic tumor models, the tumor metastasis rate in EMPCs group was the lowest. Reproduced with permission from . Copyright 2020 Elsevier Ltd.

Fig. 7

Nanosponges of circulating tumor-derived exosomes are used in combination treatment of chemotherapy and photothermal therapy for anti-metastasis. (A) Synthesis of nanosponges of circulating tumor-derived exosomes and mechanism of inhibiting breast cancer metastasis. (B) Protein analysis and FRET staining experiments on neutrophil membrane and platelet membrane confirmed the formation of hybrid membranes and the successful coating on the surface of gold nanoparticles. (C) After treatment with Exo-OVA-aCD3/aEGFR in metastatic and recurrent models, there was a large amount of CD4⁺ and CD8⁺ T cell infiltration in metastatic lung tissue, effectively preventing lung metastasis and recurrence of tumors. (D) In mice treated with PNMAuDIs in situ models, H&E staining showed almost no tumor metastasis in vital organs. Reproduced with permission from . Copyright 2020 Elsevier Ltd.

Fig. 8

Car- T like therapy based on antibody-engineered exosomes from antigen-feeding dendritic cells can inhibit metastasis. (A) Construction and mechanism diagram of anti-CD3 and anti-EGFR antibody engineering tDC-Exo (Exo-OVA-aCD3/aEGFR). (B) Characterization of Exo-OVA-aCD3/aEGFR. (C) In the model of pulmonary metastatic melanoma, Exo-OVA-aCD3/aEGFR can significantly inhibit lung metastasis of the tumor, and there is a large number of CD4⁺ and CD8⁺ T cell infiltration in metastatic lung tissue. Reproduced with permission from . Copyright 2022 Elsevier.