hUCMSC-exosomes attenuate acute lung injury by inhibiting ferroptosis in pulmonary microvascular endothelial cells through ribosomal protein RPS11 upregulation.

Summary

Nebulized hUCMSC-derived exosomes are internalized by pulmonary microvascular endothelial cells, restore mitochondrial function, and suppress ferroptosis by upregulating RPS11 and enhancing mitochondria-encoded protein translation. This multi-model, multi-omics study positions inhaled, cell-free exosomes as a therapeutic strategy to mitigate ALI/ARDS by targeting endothelial mitochondrial homeostasis.

Key Findings

• Nebulized hUCMSC-Exos are internalized by pulmonary microvascular endothelial cells in an LPS-induced ALI model.
• Exosomes reduce histologic lung injury, edema, inflammation, and endothelial ferroptosis.
• hUCMSC-Exos restore endothelial mitochondrial function via transfer of mitochondrial components.
• Proteomic analysis identifies RPS11 as the top upregulated mediator; RPS11 knockdown abrogates anti-ferroptosis and mitochondrial rescue.
• Mechanism: enhanced translation of mitochondria-encoded proteins.

Clinical Implications

Supports development of inhaled, cell-free biologics for ARDS that target endothelial ferroptosis and mitochondrial dysfunction; suggests RPS11 as a pharmacodynamic biomarker. Early-phase clinical trials should evaluate dosing, safety, and efficacy endpoints linked to ferroptosis and mitochondrial function.

Limitations

• Preclinical study without human clinical data or long-term safety outcomes.
• Sample sizes per experiment and dose–response relationships are not fully detailed.

Future Directions

Phase I/II trials of inhaled hUCMSC-exosomes in ARDS, optimization of dosing and delivery, and evaluation of RPS11/ferroptosis biomarkers alongside clinical endpoints.