Therapeutic potential of exosomes from 3D-cultured mesenchymal stem cell in a sustainable cellulose nanofibers hydrogel

Mesenchymal stem cell-derived exosomes have emerged as promising cell-free therapeutic agents in regenerative medicine due to their ability to modulate cell survival, migration and tissue repair. However, two-dimensional culture systems poorly replicate the native stem cell niche, potentially limiting the biological potency of the secreted vesicles. We propose a sustainable three-dimensional bio-based platform made from a cellulose nanofiber (CNF)-based hydrogel obtained from biorefinery process of agricultural biomass. The nanofibrillar architecture and rheological properties provide a biomimetic microenvironment that more closely resembles the native extracellular matrix compared with standard monolayer culture. In this study, an unprecedented functional evaluation was conducted by comparing Wharton's jelly-derived MSC exosomes across monolayers, scaffold-free spheroids and the CNF-Alg hydrogel. The exosomes derived from the hydrogel showed a more potent effect on the viability and migration of keratinocytes and, more significantly, on endothelial cells. These results suggest that the quality of exosomes is dictated by the architectural cues of the microenvironment rather than solely by production yield. Thus, this work establishes a new benchmark for high-performance regenerative therapies by successfully aligning advanced tissue engineering with circular economy principles.