Kidney disease is one of the growing causes of disability and death worldwide, and CKD is projected to rise to fifth place in the list of causes of death in 2040[1], [2], [3]. CKD is an important clinical event closely related to the prognosis of AKI, acute or subacute kidney injury can lead to progressive kidney dysfunction, and loss of kidney function associated with the development of CKD can lead to further episodes of AKI[4], [5]. Patients with persistent kidney dysfunction experience an irreversible loss of kidney cells and nephrons. Data on the kidney injury showed that cell death is deeply involved in the loss of kidney cells. Some newly discovered cell death mechanisms offer a fresh outlook on exploring the pathological mechanism of kidney disease. Various modes of cell death may be dynamically involved in the change of renal cell populations at multiple layers. A thorough comprehension of the mechanisms underlying cell death modes in different cell populations will aid in developing novel strategies for the treatment of kidney injury.

Cell death can be classified as accidental cell death (ACD) or RCD[6], where regulatory death occurs under physiological conditions is also known as programmed cell death (PCD). ACD is an uncontrolled process, known as necrosis, which happens when cells are exposed to injury stimuli that surpass their ability to adapt[7]. RCD involves a signaling cascade with specific biochemical, morphological, and immunological characteristics[8]. Apoptosis is the most common form of RCD caused by physiological or pathological factors and is characterized by the formation of apoptotic bodies [9]. Many emerging non-apoptotic forms of RCD (including pyroptosis, ferroptosis, parthanatos, entotic cell death, netotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, alkaliptosis and oxeiptosis) have been discovered recently and linked to various human pathologies[8]. RCD is extensively involved in the loss of renal parenchymal cells and may subsequently regulate oxidative stress, inflammatory fibrosis, and immune responses[10], [11], [12], [13]. In kidney disease, the transmission and regulation of cell death signals have always been the focus of research. EVs are rich in bioactive substances (such as genomic DNA, messenger RNA, circular RNA, long non-coding RNA, microRNA, proteins, and lipids), which makes it a vital medium for transmitting the death signal to kidney cell population.

EVs are lipid-bilayer membrane-enclosed vesicles that are secreted by all cell types under both normal and pathological conditions[14]. EVs are heterogeneous in terms of size, content and source, and the classification of EVs is continuously evolving[15]. Based on the origin and biogenesis of EVs, three major modes of biogenesis are currently known: apoptotic EVs are released as fragments of cells undergoing apoptosis (are divided into larger apoptotic bodies (1-5μm) and smaller apoptotic vesicles (100-1000 nm)), ectosomes are derived from outward budding from the plasma membrane (mostly ranging in size from 200 to 1000 nm), and exosomes are formed through the fusion of multivesicular bodies (MVBs) and the cell membrane (ranging from 30-150 nm in diameter)[16], [17], [18], [19]. International Extracellular Vesicle Society (ISEV) suggested that EVs can be divided into small-sized vesicles (sSVs) with a particle size less than 200 nm and medium/large EVs with a particle size greater than 200 nm[20]. The study of EVs is a rapidly expanding research field. Migrasomes (500-3000 nm) are newly discovered EVs that are released from the retraction fibers of migrating cells[21], they may function to remove damaged mitochondria from cells and mediate intercellular communication[22], [23]. Recent discoveries have revealed two non-vesicular extracellular nanoparticles (NVEPs), exomeres and supermeres. Exomeres are highly enriched in metabolic enzymes and signature proteins involved in glycolysis and mTORC1 signaling[24]. Supermeres have been examined to be the smallest member of the family of NVEPs so far and they may exhibit a more significant enrichment of small RNA than both EVs and exomeres[25]. The biosynthesis and intercellular communication of EVs have been illustrated in Fig. 1 and the biogenesis of exomeres and supermeres is unknown.

The membrane vesicle structure of EVs facilitates the encapsulation of signal molecules such as proteins, lipids and nucleic acids, avoiding the rapid degradation of these signal molecules, so as to achieve local and long-distance intercellular communication. The study of endogenous EVs in kidney mainly focuses on the application of vesicle-derived RNA and protein as biomarkers in minimally invasive liquid biopsies and in evaluating the prognosis of kidney disease[26]. Exogenous mesenchymal stem cells derived-EVs (MSC-EVs) have shown therapeutic potential in reducing inflammation, promoting regeneration and inhibiting fibrosis[27], and engineering modified MSC-EVs further enhance the effectiveness of EV therapy.

Here, we provide a critical review of EV-mediated renal apoptosis and non-apoptotic forms of RCD (pyroptosis, necroptosis, ferroptosis) in terms of pathogenesis and treatment of AKI and CKD, and summarize a variety of engineered EV strategies for precise regulation of renal cell apoptosis. Overall, EVs-mediated novel RCD regulation of kidney disease has optimistic prospects. We hope that this review could provide detailed overview and comprehensive understanding for further research.