Organoid extracellular vesicle-based therapeutic strategies for bone therapy

doi:10.12336/biomatertransl.2023.04.002

Biomaterials Translational ›› 2023, Vol. 4 ›› Issue (4): 199-212.doi: 10.12336/biomatertransl.2023.04.002

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Organoid extracellular vesicle-based therapeutic strategies for bone therapy

Han Liu¹^,²^,³^,⁴, Jiacan Su¹^,²^,³^,⁴^,^*()

1 Institute of Translational Medicine, Shanghai University, Shanghai, China
2 Organoid Research Center, Shanghai University, Shanghai, China
3 National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai, China
4 Department of Orthopedics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Received:2023-09-30 Revised:2023-11-24 Accepted:2023-12-05 Online:2023-12-27 Published:2023-12-28
Contact: Jiacan Su, drsujiacan@163.com.

Abstract

Abstract:

With the rapid development of population ageing, bone-related diseases seriously affecting the life of the elderly. Over the past few years, organoids, cell clusters with specific functions and structures that are self-induced from stem cells after three-dimensional culture in vitro, have been widely used for bone therapy. Moreover, organoid extracellular vesicles (OEVs) have emerging as promising cell-free nanocarriers due to their vigoroso physiological effects, significant biological functions, stable loading capacity, and great biocompatibility. In this review, we first provide a comprehensive overview of biogenesis, internalisation, isolation, and characterisation of OEVs. We then comprehensively highlight the differences between OEVs and traditional EVs. Subsequently, we present the applications of natural OEVs in disease treatment. We also summarise the engineering modifications of OEVs, including engineering parental cells and engineering OEVs after isolation. Moreover, we provide an outlook on the potential of natural and engineered OEVs in bone-related diseases. Finally, we critically discuss the advantages and challenges of OEVs in the treatment of bone diseases. We believe that a comprehensive discussion of OEVs will provide more innovative and efficient solutions for complex bone diseases.

Key words: bone therapy, engineering modifications, extracellular vesicles, nanotechnology, organoid extracellular vesicles

Cite this article

Figures/Tables 11

Figure 1. Schematic illustration of organoid extracellular vesicle (OEV)-based bone disease treatment strategy. OEVs have emerging as promising cell-free nanocarriers for bone therapy due to their vigoroso physiological effects, significant biological functions, stable loading capacity, and great biocompatibility. Created with BioRender.com.

Figure 2. Biogenesis and internalisation of organoid extracellular vesicles (OEVs). The early endosome was formed by the absorption of extracellular proteins by the plasma membrane through endocytosis. The early endosome gradually matured into the late endosome by exchanging goods with the endoplasmic reticulum and Golgi apparatus. In the late endosomes, a second plasma membrane invasion occurs to form multivesicular body (MVB), which is finally selected to fuse with the plasma membrane of the cell to release OEVs or to fuse with lysosomes with the participation of sorting proteins. The free OEVs arrive at the recipient cell and are absorbed by endocytosis or receptor ligand binding. Created with BioRender.com.

Figure 3. Isolation of organoid extracellular vesicles (OEVs). After three-dimensional (3D) cultivation, the organoid culture is collected and centrifuged at 10,000 × g for 15 minutes at 4°C. The supernatant is then filtered by 0.22 μm sterile filter to remove impurities. Subsequently, OEVs precipitate are collected by the ultracentrifugation for 2 hours at 150,000 × g. The collected OEVs are purified with phosphate buffered saline (PBS) and ultracentrifuged at 150,000 × g for 2 hours. The obtained OEVs can be characterised and verified using nanoparticle tracking analysis, transmission electron microscopy, and Western blotting to represent the size, shape, concentration, and specific markers of OEVs. The collected OEVs are used immediately or stored at –80°C until use. Created with BioRender.com.

Table 1. The extraction methods of organoid extracellular vesicles

Method	Principle	Advantage	Disadvantage	Reference
Gradient ultrafast centrifugation	Different settlement coefficient	High purity; Separable subgroup	Time-consuming; High equipment requirements	48
Volume exclusion chromatography	Different particle size	High purity; Fast preparation	Expensive; Low output	49
Immunoaffinity capture	Specific binding	High purity; Specific exosomes	Expensive; Need to optimise ligand; Low yield	50
Microfluidic technology	Immunoaffinity, particle size and density	High efficiency; No chemical pollution	Low yield; Expensive	51
EVs extraction kit	Immune magnetic bead capture	Simple method	Low output; Expensive	-
Sucrose density gradient centrifugation method	Centrifugal force	High purity	Low output; Long time; Tedious process	52

Figure 4. The differences between organoid extracellular vesicles (OEVs) and traditional extracellular vesicles (EVs). Two-dimensional (2D) cultured cells produced fewer EVs, poor bioactivity, and less protein and nucleic acid (left), while three-dimensional (3D) cultured cells produced more OEVs, more active, and more protein and nucleic acid (right). Created with BioRender.com. miRNA: microRNA.

Figure 5. The application diagram of organoid extracellular vesicles (OEVs). OEVs have a wide range of applications, including liquid biopsy, pharmacological testing, toxicity testing, disease treatment, customised personalised medicine, genetic research. Created with BioRender.com.

Figure 6. Organoid extracellular vesicles (OEVs) for disease treatment. (A) OEVs secreted by intestinal organoids can exert anti-inflammatory effects, while the anti-inflammatory effects of secreted OEVs are lost after the use of opioids acting on organoids. Created with BioRender.com. (B) Cultivation and collection of SG-like organ (SGO) by magnetic 3D bio-assembly (M3DB) system for the treatment of radiation-induced epithelial damage. Reprinted from Chansaenroj et al.79 3D: three-dimensional; 96w ULP: 96-well ultra-low attachment plate; CM: conditioned media; EV: extracellular vesicle; FGF10: fibroblast growth factor 10; GM: growth media; hDPSC: human dental pulp stem cell; IR: irradiated; NTA: nanoparticle tracking analysis; SG: salivary gland; TEM: transmission electron microscopy; WB: Western blotting.

Figure 7. The engineering approaches for modifying organoid extracellular vesicles (OEVs), including the engineering parental cells and engineering OEVs after isolation. Engineering parental cells, such as using clustered regularly interspaced short palindromic repeats-CRISPR-associated protein 9 (CRISPR-Cas9) to modify cells to obtain engineered organoids. Engineering OEVs after isolation are mainly Electroporation, chemical engineering, membrane fusion, and freeze thaw. Created with BioRender.com.

Table 2. Engineered retrofit solutions for organoid extracellular vesicles

Engineering approach	Strategy	Method	Purpose	Reference
Engineering parental cells	Genetic engineering	Direct modification of parent cells	The protein was displayed on the surface of extracellular vesicles to enrich its physiological function	53
	Synthetic biology	Shuttle plasmid	Giving new functionality to bacterial extracellular vesicles	11
Engineering after isolation	Membrane fusion	Co-incubation	Loading of exogenous cargo into the membrane	87
	Chemical engineering	Non-covalent reaction	Increased extracellular vesicles targeting	88
	Chemical engineering	Click chemistry	Loading of azides onto the membrane surface	89
	Freeze-thaw	Freeze-thaw cycle	Loading extracellular vesicles with exogenous substances and ensuring normal morphology	90
	Electroporation technique	High voltage electric field	Transfer of DNA, or/and RNA into extracellular vesicles	11

Figure 8. Engineering parental cells to endow their extracellular vesicles (EVs) with powerful functions. (A) Schematic illustration of exosome-guided microRNA (miRNA) blocking. Reprinted from Hu et al.53 (B) Schematic illustration of the construction of bioengineered bacterial EVs (BEVs). Reprinted from Liu et al.11 Copyright 2023, with permission from Elsevier. BEV: bacterial extracellular vesicle; BEV-C: BEVs-hCXCR4; BEV-CS: BEVs-hCXCR4-SOST siRNA; ClyA: A bacterial surface protein; CXCR4: C-X-C motif chemokine receptor 4; ECN: construct probiotic Escherichia coli Nissle 1917; hCXCR4: human C-X-C motif chemokine receptor 4; IV: intravenous; p: plasmid; SDF1: stromal cell-derived factor 1; siRNA: small interfering RNA; SOST: sclerostin.

Figure 9. Advantages and challenges of organoid extracellular vesicles (OEVs). OEVs have the advantages of strong physiological function, high yield, low immunogenicity, cell-free system, and good delivery potential. At the same time, OEVs also have several obstacles, including unknown functional mechanism, lack of source, need engineering transformation, single function, and lack of standardised extraction course. Created with BioRender.com.

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[1]	Xiaoxiang Ren, Ruixue Xu, Chenjie Xu, Jiacan Su. Harnessing exosomes for targeted therapy: strategy and application [J]. Biomaterials Translational, 2024, 5(1): 46-58.
[2]	Zhao–Lin Zeng, Hui Xie. Mesenchymal stem cell–derived extracellular vesicles: a possible therapeutic strategy for orthopaedic diseases: a narrative review [J]. Biomaterials Translational, 2022, 3(3): 175-187.

Organoid extracellular vesicle-based therapeutic strategies for bone therapy

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