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

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.