Therapeutic Potential of Extracellular Vesicles for Sepsis Treatment

Abstract

Sepsis is a deadly condition lacking a specific treatment despite decades of research. This has prompted the exploration of new approaches, with extracellular vesicles (EVs) emerging as a focal area. EVs are nanosized, cell-derived particles that transport bioactive components (i.e., proteins, DNA, and RNA) between cells, enabling both normal physiological functions and disease progression depending on context. In particular, EVs have been identified as critical mediators of sepsis pathophysiology. However, EVs are also thought to constitute the biologically active component of cell-based therapies and have demonstrated anti-inflammatory, anti-apoptotic, and immunomodulatory effects in sepsis models. The dual nature of EVs in sepsis is explored here, discussing their endogenous roles and highlighting their therapeutic properties and potential. Related to the latter component, prior studies involving EVs from mesenchymal stem/stromal cells (MSCs) and other sources are discussed and emerging producer cells that could play important roles in future EV-based sepsis therapies are identified. Further, how methodologies could impact therapeutic development toward sepsis treatment to enhance and control EV potency is described.

Bolstering the secretion and bioactivities of umbilical cord MSC-derived extracellular vesicles with 3D culture and priming in chemically defined media

“…Further, there have been reports that the properties of MSC-derived EVs can be tuned with the culture environment of the cells [23,24]. EVs from MSC with three-dimensional (3D) cell aggregates (referred to as spheroids) exhibit not only high production yield but an enhanced expression of cytokines associated with immunosuppression and anti-apoptotic properties compared to conventional two-dimensional (2D) culture [25,26]. Moreover, it has been expected to release EVs with much higher similarity to in vivo circulating EVs due to the proximities of cell environments [27].…”

Role of extracellular microRNA-146a-5p in host innate immunity and bacterial sepsis

“…Extracellular vesicles (EVs) are natural carriers for plasma miRNAs ( Thery et al., 2002 ). Our recent work has revealed that miR-146a-5p expression is upregulated in septic plasma EVs and may contribute to the proinflammatory effect of septic EVs ( Kronstadt et al, 2021 ; Xu et al., 2018 ). Indeed, HEK293T EVs loaded ss miR-146a-5p mimics induced a robust CXCL2, TNFα, and IL-6 production in BMDMs ( Figure 3 E).…”

Bioengineered extracellular vesicles: future of precision medicine for sepsis

“…Research of endogenous EVs and their specific roles in sepsis progression reveal numerous diagnostic capabilities in pre-clinical sepsis models, as well as in human patients [56]. As mentioned above, EVs plasma levels in general have been proposed as predictive biomarkers for organ failure and mortality rate of septic patients [22], as well as, specific miRNA expression profile in EVs from septic patients, that has been also associated with sepsis survival and disease stage [57].…”