Safety and Anti‐Inflammatory Effects of Engineered Extracellular Vesicles (ILB‐202) for NF‐κB Inhibition: A Double‐Blind, Randomized, Placebo‐Controlled Phase 1 Trial

ABSTRACT Excessive activation of NF‐κB is implicated in the pathogenesis of numerous inflammatory and autoimmune diseases; however, conventional NF‐κB inhibitors often cause widespread immunosuppression. In contrast, extracellular vesicles (EVs) are promising vehicles for therapeutic cargo delivery with advantages including reduced risk of replication. In this single‐centre, randomized, double‐blind, placebo‐controlled phase 1 trial, we evaluated ILB‐202, an engineered, allogeneic EV derived from HEK293 cells and loaded with a super‐repressor IκBα. A single ascending intravenous dose of ILB‐202 was administered to 18 healthy volunteers, and the short‐term safety, tolerability, and preliminary pharmacodynamic effects were assessed. ILB‐202 was well tolerated at all dose levels with no serious or dose‐limiting toxicities; only minor adverse events, including a mild decrease in NK cell counts and one case of grade 1 neutropenia, were observed. The laboratory parameters, vital signs and cytokine profiles remained stable, indicating no systemic immunogenicity. Single‐cell RNA sequencing revealed subtle, time‐dependent modulation of NF‐κB‐associated pathways, enhanced TGF‐β and visfatin signalling and reduced TNF signalling—suggesting a shift towards an anti‐inflammatory state. These findings support the safety and immunomodulatory activity of ILB‐202 and pave the way for future trials in diseases characterized by dysregulated NF‐κB activation. Trial Registration : ClinicalTrials.gov identifier: NCT05843799