Oral connexin43-peptide-loaded milk extracellular vesicles mitigate lethal radiation injury while preserving tumour radiosensitivity.

Ionizing radiation is central to cancer therapy, where normal-tissue toxicity limits dose escalation, and is also a major hazard in accidental or mass-casualty exposures, where practical radiomitigators for radiosensitive organs are urgently needed. We investigated orally delivered milk extracellular vesicles (mEVs) loaded with the connexin43 carboxyl-terminal peptide αCT11 (XOlacta) in a murine 14 Gy total-body irradiation model and a syngeneic GL261 glioma radiotherapy model. A single oral XOlacta dose given 1 h after total-body irradiation conferred 42% 30-day survival despite an expected 100% lethality from a 14 Gy challenge, with marked preservation of ileal architecture and femoral bone marrow cellularity, and significant benefit was retained when dosing was delayed to 24 h. Biodistribution studies with fluorescently labeled mEVs showed radiation-enhanced uptake in brain, gut, and bone marrow, consistent with injury-licensed targeting of radiosensitive tissues. In glioma-bearing mice, XOlacta protected normal tissues without diminishing tumour radiosensitivity. These findings identify oral αCT11-loaded mEVs as a potent, non-parenteral radiomitigator that preserves normal-tissue integrity while maintaining tumour response in a therapeutic context, and support connexin-linked mEV-targeting as a promising strategy for both radiotherapy adjuncts and management of high-dose radiation exposures.