3D bioprinting meets nanotherapeutics: a vehicle for sustained extracellular vesicle delivery.

Abstract

Extracellular vesicles (EVs) are naturally occurring nanoparticles that mediate intercellular communication and hold great promise as a cell-free therapeutic strategy for kidney disease. However, their clinical translation remains limited by rapid clearance and inefficient tissue targeting. To overcome these challenges, we developed a decellularized kidney extracellular matrix (DKECM)-based bioink capable of sustained EV delivery. Unlike existing bioinks that combine extracellular matrix with other biomaterials, this formulation uses DKECM alone, preserving renal-specific bioactivity. We report the first successful isolation and characterization of EVs from human renal progenitor cells (RPCs), confirmed by nanoparticle tracking analysis, cryo-electron microscopy, and enrichment of specific-EV markers. Functionally, RPC-derived EVs were readily internalized by tubular epithelial cells and modulated oxidative stress, proliferation, and injury responses under hypoxic conditions. The DKECM based-bioink exhibited shear-thinning behavior, high shape fidelity, and efficient layer stacking, supporting precise bioprinting and gradual EV release over two weeks. This system recreates key features of the renal microenvironment, providing a platform for controlled, localized EV delivery. In summary, this study introduces a fully extracellular matrix-derived bioink that enables sustained EV release and maintains renal bioactivity, offering a promising strategy for biofabrication approaches in kidney repair and regeneration.