Engineered Red Blood Cell-Derived Extracellular Vesicles With Klotho Peptide Protect the Kidney From Fibrosis

Area of Science:

• Biomedical Engineering
• Nephrology
• Regenerative Medicine

Background:

• Chronic kidney disease (CKD) involves progressive tubular injury and fibrosis, leading to kidney function loss.
• Extracellular vesicles (EVs) offer biocompatible and engineerable platforms for therapeutic delivery.
• Targeting fibrosis is crucial for preserving renal function in CKD.

Purpose of the Study:

• To engineer red blood cell-derived EVs to deliver an active peptide from klotho.
• To develop a targeted antifibrotic strategy for kidney fibrosis using engineered EVs.
• To evaluate the efficacy of klotho-engineered EVs in preclinical models of kidney fibrosis.

Main Methods:

• Isolation and surface functionalization of red blood cell-derived EVs with a klotho peptide (RBC-EVKP1).
• Evaluation of fibrosis in proximal tubular epithelial cells stimulated with TGFβ.
• Assessment of RBC-EVKP1 in a 3D proximal tubule-on-chip model under fibrotic conditions.

Main Results:

• RBC-EVKP1 significantly attenuated TGFβ-induced fibrotic gene expression and extracellular matrix accumulation.
• Engineered EVs suppressed SMAD signaling, reduced cell migration, and preserved epithelial organization.
• In the tubule-on-chip model, RBC-EVKP1 maintained cytoskeletal integrity and reduced injury markers.

Conclusions:

• Klotho-engineered EVs demonstrate potent antifibrotic effects against TGFβ-driven fibrosis.
• This strategy effectively preserves tubular integrity, offering a promising therapeutic avenue for CKD.
• Engineered EVs represent a viable platform for targeted antifibrotic therapy in kidney disease.