Exosomes and the NLRP3 Inflammasome: A Bidirectional Axis in Cellular Signaling and Vesicle Trafficking in Health and Disease

Abstract

Exosomes are small extracellular vesicles (EVs) generated through the endosomal pathway that mediate intercellular communication by transferring proteins, lipids, and regulatory RNAs. In parallel, the NLRP3 inflammasome is a key signaling platform of the innate immune system that integrates cellular stress signals to drive inflammatory responses. Recent studies suggest that exosome biology and NLRP3 signaling intersect at fundamental levels of cell organization. On one hand, inflammasome activation can promote exosome biogenesis and secretion through caspase-1-dependent remodeling of intracellular trafficking, including cleavage of Rab-interacting lysosomal protein (RILP) and redistribution of multivesicular bodies (MVBs). These processes influence the selective loading of exosomal cargo, notably miRNAs, through sequence-dependent mechanisms involving RNA-binding proteins and the endosomal sorting machinery. Conversely, exosomes can modulate inflammasome activity in recipient cells by delivering regulatory molecules that affect NLRP3 priming and signaling. Although exosome release is increased in several inflammatory disorders, including ischemia/reperfusion injury, diabetes and neurodegenerative disease, the mechanistic relationship between exosome pathways and NLRP3 remains incompletely understood. In addition to their pathogenic and diagnostic relevance, exosomes are increasingly being explored as innovative acellular biologics and therapeutic delivery platforms due to their immunomodulatory and regenerative properties. In particular, mesenchymal stem cell (MSC)-derived exosomes have shown promising anti-inflammatory effects through modulation of NLRP3 pathways in preclinical models of kidney, cardiovascular, neurological and inflammatory diseases. Here, we review current evidence connecting NLRP3 inflammasome activation to EV trafficking, exosome formation, and cargo selection, and discuss how exosome-mediated communication shapes inflammasome signaling across cells and tissues in health and disease.