Chondrocyte-mimetic therapeutic microcarriers for synergistic chemo-mechanical signaling in cartilage regeneration

Traumatic and degenerative cartilage injuries pose a significant clinical challenge. Among emerging treatments, cell-free, tissue-mimicking approaches have shown promise for cartilage regeneration. Here we design chondrocyte-mimicking therapeutic microcarriers that stimulate host chondrocyte migration, proliferation, and maturation by recapitulating the native chondrogenic niche. Our microcarriers, featuring an interconnected microporous network, are functionalized with chondrocyte-derived cell membrane and chondrocyte-secreted exosome. The microcarrier framework provides structural support at the defect site while allowing cell anchorage and infiltration. The chondrocyte-derived cell membrane, replicating the native chondrocytes, retains cartilage-specific extracellular matrix (ECM), and serves as a reservoir for exosome delivery, facilitating anabolic responses through integrin-mediated mechanotransduction, particularly <i>via</i> the Rho/ROCK-actin-YAP axis. Furthermore, the chondrocyte-derived exosomes restore cartilage homeostasis by delivering chondrogenic miRNAs and regulating key metabolic processes, including lipid metabolism and ECM remodeling. Together, these therapeutic components play a synergistic role in driving chemo-mechanical signaling, promoting chondrocyte recruitment, proliferation, and maturation, ultimately coordinating cartilage repair. This biomimetic approach offers a promising strategy for cell-free cartilage regenerative therapies.