Synergistic interplay of dECM and exosomes in shaping the cartilage matrix microenvironment: A new paradigm for regenerative medicine

• dECM-exosome integration mimics the native cartilage microenvironment for regeneration. • Exosomes deliver bioactive signals to enhance chondrogenesis and immune modulation. • dECM scaffolds retain exosomes, enabling sustained release for cartilage regeneration. • Microfluidic and organoid models reveal dECM-exosome interactions in cartilage repair. • Engineered exosomes modulate epigenetics for precise cartilage gene activation. This comprehensive review explores integrative approaches combining decellularized extracellular matrix (dECM) with exosome-based therapies to target structural integrity and biochemical signaling to promote cartilage regeneration. dECM is a biomimetic scaffold that retains essential components such as collagen and proteoglycans, which are crucial for cellular adhesion, matrix maintenance, and cartilage formation. Exosomes, on the other hand, derived from mesenchymal stem cells, enhance intercellular communication by delivering bioactive molecules such as growth factors and microRNAs. Combining dECM with exosomes can precisely mimic the cartilage matrix microenvironment, simultaneously promoting cell growth and the production of matrix components and modulating responses. This review delves into the mechanisms of dECM-exosome interactions, innovative integration technologies, and their impact on gene expression and cartilage-specific cellular responses. We demonstrate the potential of dECM-exosome therapy to enhance cartilage repair through in vitro and in vivo studies. Ultimately, these findings lay the foundation for the next-generation of cell-matrix-based therapeutics, which will provide advanced therapeutic strategies to improve clinical outcomes for cartilage damage and degenerative joint diseases. The synergistic integration of decellularized extracellular matrix (dECM) and exosomes creates a self-sustaining regenerative microenvironment. dECM activates chondrogenic signaling, while exosomes enhance bioactive cargo distribution within a protective niche that promotes angiogenesis, immunomodulation, chondrogenic differentiation, matrix stability, and tissue maturation. This interaction drives dECM remodeling, enhances bioactivity, and supports native-like cartilage formation, offering a promising regenerative medicine strategy.