Engineered Extracellular Vesicles in Chronic Kidney Diseases: A Comprehensive Review

Abstract

Chronic kidney diseases (CKD) present a formidable global health challenge, characterized by a deficiency of effective treatment options. Extracellular vesicles (EVs), recognized as multifunctional drug delivery systems in biomedicine, have gained accumulative interest. Specifically, engineered EVs have emerged as a promising therapeutic approach for targeted drug delivery, potentially addressing the complexities of CKD management. In this review, we systematically dissect EVs, elucidating their classification, biogenesis, composition, and cargo molecules. Furthermore, we explore techniques for EV engineering and strategies for their precise renal delivery, focusing on cargo loading and transportation, providing a comprehensive perspective. Moreover, this review also discusses and summarizes the diverse therapeutic applications of engineered EVs in CKD, emphasizing their anti-inflammatory, immunomodulatory, renoprotective, and tissue-regenerating effects. It critically evaluates the challenges and limitations in translating EV therapies from laboratory settings to clinical applications, while outlining future prospects and emerging trends.

Keywords: application; chronic kidney diseases; drug delivery systems; extracellular vesicles; nanomaterials.

Figure 1

The present paper overview of chronic kidney disease (CKD) pathology, explores the involvement of extracellular vesicles (EVs) in CKD progression and therapy, and examines the methods of enhancing EV function through Engineered EVs, along with their potential application in treating CKD. The pink arrows represent the components of CKD. The red arrow represents kidney derived from people.

Figure 2

EVs originating from various sources such as stem cells, the kidney, and other organs play a crucial role in regulating both the physiological functions and pathological processes within the kidney. Additionally, EVs derived from plasma hold potential as biomarkers for detecting CKD. The pink arrow represents EVs could be transported to kidney. The brown arrows represent the biogenesis and release of EVs.

Figure 3

Strategies for modifying endogenous EVs for therapeutic cargo incorporation.

Figure 4

The therapeutic potential of TNF-α/interferon-γ (IFN-γ)-primed MSC-derived extracellular vesicles (TI-EVs) in chronic kidney disease involves inflammation suppression. (A) A schematic representation illustrating the utilization of TI-EVs within a bioactive scaffold for kidney tissue regeneration, focusing on inflammation and fibrosis suppression. (B) Morphological, size, and surface marker characteristics of TI-EVs demonstrated. Scale bars indicate 100 nm. (C) Quantitative analysis comparing CD9, CD63, and CD81 expression levels in TI-EVs and unconditioned MSC-derived EVs (UC-EVs). (D) Confocal immunofluorescence images displaying Arg1 expression in LPS/IFN-γ-stimulated RAW264.7 cells post-treatment with PDRN and/or TI-EVs. (E). Immunofluorescence images depicting CD206 expression two weeks after scaffold implantation. The arrows indicate the different components were incorporated into scaffold. Reprinted with permission from Ko KW, Park SY, Lee EH, Yoo YI, Kim DS. Integrated bioactive scaffold with polydeoxyribonucleotide and stem-cell-derived extracellular vesicles for kidney regeneration. ACS Nano. 2021;15(4):7575–7585. Copyright 2021 American Chemical Society.

Figure 5

MSC-EVs-CHIP alleviate fibrosis through CHIP delivery. (A) TEM images: MSC-EVs and MSC-EVs-CHIP. Scale: 100 nm. Size measured by DLS. (B) Immunofluorescence: α-SMA (Red), Slc5a1 (Green), DAPI (Blue) (Upper). Fibronectin via immunohistochemistry (Middle). HE staining for renal inflammation. CD66 (Red) for inflammatory infiltration. DAPI (Blue) for nuclei. Scale: 100 µm (Below). (C) Renal tissue images: UUO rats (n = 6/group), treatments: sham, PBS, MSC-EVs (10 mg/kg), MSC-EVs-CHIP (10 mg/kg). (D) Sirius red staining: n = 3, higher magnification. Scale: 1 mm (top), 100 µm (bottom). (E) Masson trichrome staining: renal tissue sections, n = 3. Scale: 100 µm. Reprinted with permission from Ji C, Zhang J, Shi L, et al. Engineered extracellular vesicle-encapsulated CHIP as novel nanotherapeutics for treatment of renal fibrosis. NPJ Regen Med. 2024;9(1):3. Under Creative Commons CC BY License.

Figure 6

Diagram demonstrating the preparation process of Pc/C5A@EV (A) and its application in conducting simultaneous hypoxia-sensitive imaging and therapeutic intervention in injured kidneys (B). The arrows represent the next synthesis process of Pc/C5A@EV. Reprinted with permission from Cheng YQ, Yue YX, Cao HM, et al. Coassembly of hypoxia-sensitive macrocyclic amphiphiles and extracellular vesicles for targeted kidney injury imaging and therapy. J Nanobiotechnol. 2021;19(1):451. Under Creative Commons CC BY License.