Extracellular vesicles-loaded DNA hydrogels: A promising candidate for cartilage organoids engineering

Articular cartilage lesion such as osteoarthritis (OA) is becoming a serious threat to global human health. In recent years, as a new paradigm in cartilage tissue engineering and regenerative medicine, cartilage organoids (CORGs) have shown great potential in cartilage development, pathological mechanisms research and therapeutic drugs development. Functional biomaterials, especially defined hydrogels have been employed in constructing artificial extracellular matrix by precisely regulating physicochemical properties to form 3D microenvironment conducive to cells self-organization and CORGs formation. DNA hydrogels are hydrophilic polymer network formed by cross-linked DNA chains, which have good biocompatibility, biodegradability, sequence designability and adjustable versatility. Based on these advantages, DNA hydrogels not only can accurately regulate the chemical compositions, mechanical properties, topologies and respond spatiotemporally to external signals to guide cell behaviors, but also bear excellent drugs delivery ability for tissue regeneration. As a result, we believe that DNA hydrogels have great advantages for CORGs development and further application. Extracellular vesicles (EVs) from different sources have been proved to be an advance therapy for OA and significantly promote cartilage regeneration through multiple mechanisms. Engineering strategies such as directly modifying EVs or combining biomaterials have been applied to enhance efficacy of EVs. Thus, EVs as multifunctional bioactive components may play a key role in accelerating CORGs formation. In this review, we proposed an innovative strategy: EVs-loaded DNA hydrogels as promising candidate for CORGs construction and application. It is hoped that this review can provide a new insight for researchers and clinicians engaged in CORGs related research.