Excessive activation of NF-κB is implicated in the pathogenesis of numerous inflammatory and autoimmune disease; 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-center, 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 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 TGFβ and visfatin signaling and reduced TNF signaling—suggesting a shift toward 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. The trial is registered at ClinicalTrials.gov (ID number NCT05843799).

C.C. is the founder and shareholder of ILIAS Biologics, Inc.; H.C. is the shareholder and ex-employee of ILIAS Biologics, Inc.; S.H, D.H, S-H.A., K.C., S.R. and C.P. are employee of ILIAS Biologics, Inc. The remaining authors declare no competing interests.

NCT05843799

This study was supported by a grant from the Drug Development Program through the Korea Health Industry Development Institute (HI20C0170), funded by the Ministry of Health and Welfare, Republic of Korea.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics committee of Bellberry Human Research Ethics Committee gave ethical approval for this work.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

This study was supported by a grant from the Drug Development Program through the Korea Health Industry Development Institute (HI20C0170), funded by the Ministry of Health and Welfare, Republic of Korea.C.C. is the founder and shareholder of ILIAS Biologics, Inc.; H.C. is the shareholder and ex-employee of ILIAS Biologics, Inc.; S.H, D.H, S-H.A., K.C., S.R. and C.P. are employee of ILIAS Biologics, Inc. The remaining authors declare no competing interests.

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.