Neutrophil membrane engineered HucMSC sEVs alleviate cisplatin-induced AKI by enhancing cellular uptake and targeting

Abstract

Human umbilical cord mesenchymal stem cells-derived small extracellular vesicles (hucMSC-sEVs) have been demonstrated as a therapeutic agent to prevent and treat cisplatin-induced acute kidney injury (AKI). However, hucMSC-sEVs still face many problems and challenges in the repair and treatment of tissue injury, including short circulation time, insufficient targeting, and low therapeutic efficacy. Therefore, we constructed engineered hybrid vesicles fused with nanovesicles derived from human neutrophil membranes and hucMSC-sEVs, named neutrophil membrane engineered hucMSC-sEVs (NEX). NEX significantly enhanced the targeting of hucMSC-sEVs to injured kidney tissues, improved the impaired renal function via reducing pro-inflammatory cytokines expression, promoted the proliferation of renal tissue cells, and inhibited renal cell apoptosis in vivo. In addition, NEX enhanced hucMSC-sEVs uptake by NRK52E cells, but inhibited its uptake by RAW264.7 cells. Moreover, administration of NEX reduced cellular oxidative stress and promoted proliferation of NRK52E cells treated with cisplatin in vitro. In summary, our findings indicate that this design of a universal approach enhances the targeting and therapeutic efficacy of hucMSC-sEVs in kidney tissue regeneration, and provides new evidence promoting its clinical application.

Systems Approaches to Cell Culture-Derived Extracellular Vesicles for Acute Kidney Injury Therapy: Prospects and Challenges

“…The difference in cell-specific uptake was attributed to CD47, which was found on neutrophil membranes but not MSC-EVs. 189 …”

Advances in the application of extracellular vesicles derived from three-dimensional culture of stem cells

“…Here we present 3D culture of umbilical cord-derived SCs, mainly UCMSCs and umbilical cord blood MSCs (UCBMSCs). Similar to BMMSC-EVs, EVs derived from 2D cultured UCMSCs have been found to exert protective effects in various ways, such as acute and chronic renal injury, heart injury, liver injury, brain injury, and immunomodulation, as well as alleviation of type 2 diabetes mellitus [ 23 , 173 – 179 ]. As with BMMSCs, in an in vivo wound healing model, EVs derived from 3D spheroid culture and 3D spinner flask culture of UCMSCs were able to promote epithelialization of wounds and accelerate post-injury skin healing, with a more dramatic effect than 2D-EVs [ 147 , 163 ].…”

“…EVs derived from 2D cultured hucMSCs suffered from low yield and limited therapeutic effect in the treatment of acute kidney injury (AKI) [ 23 , 28 ]. Therefore, Cao et al applied the hollow fiber bioreactor to culture hucMSCs, and the same number of hucMSCs harvested exosomes 19.4-fold higher than those harvested from cells cultured in conventional 2D culture.…”

“…SCs exert therapeutic effects mainly through their paracrine functions, and EVs are important effectors of their paracrine effects [ 17 ]. Numerous experimental studies showed that EVs derived from SCs (SC-EVs), especially mesenchymal stromal cells (MSCs), also known as mesenchymal stem cells [ 18 ], played a significant role in the treatment of respiratory diseases [ 19 , 20 ], kidney diseases [ 21 – 23 ], liver diseases [ 24 , 25 ], neurological diseases [ 26 ], cardiovascular diseases [ 27 ], and other diseases. As a cell-free component, EVs have high structural and compositional stability, and the ability to target injured cells, overcoming the shortcomings of stem cell therapy [ 8 ].…”

Extracellular vesicles in chronic kidney disease: diagnostic and therapeutic roles

“… Tang et al, 2021 established a red blood cell-derived EVs (RBCEVs)based drug delivery platform and conjugated Kim-1-targeting LTH peptides to RBCEVs to target renal tubular injury. In addition, Wu et al constructed a neutrophil membrane-engineered nanoparticle (NEX) that significantly promoted targeted enrichment of EVs in damaged renal tissue, thereby improving AKI ( Wu et al, 2022 ). In addition, various hybrid approaches from tumor treatment models have provided valuable insights for targeted EV therapy in CKD.…”