Extracellular vesicles redefine immune modulation through Toll-like receptor networks.

INTRODUCTION: Extracellular vesicles (EVs) are potent immunomodulators that can promote the transition from pro-inflammatory to regulatory immune responses across diverse pathological conditions. Tissue injury increases the release of damage- and pathogen-associated molecular patterns (DAMPs and PAMPs), which activate Toll-like receptors (TLRs) to rapidly initiate inflammatory and antiviral responses. Here, we propose that TLR signaling serves as a central axis through which EVs exert both pathogenic and therapeutic effects. AREAS COVERED: This review summarizes current evidence on EV crosstalk with surface and endosomal TLRs and discusses how these interactions may drive long-term reprogramming of target cells. We highlight lipid raft signaling as a unifying mechanism linking TLRs and other receptors to signaling hubs controlling pro- and anti-inflammatory responses. Finally, we propose a model in which EVs act as inducers of trained immunity in immunocompetent cells. EXPERT OPINION: EVs have emerged as key immunomodulators that transport diverse DAMPs, transmit danger signals to surrounding tissues, and may establish trained immunity, priming cells for subsequent insults. Conversely, therapeutic EVs can target hyperinflammatory cells by modulating aberrant TLR signaling and reprogramming them toward a restorative, pro-resolving phenotype.