Hybrid SMART spheroids to enhance stem cell therapy for CNS injuries

Although stem cell therapy holds enormous potential for treating debilitating injuries and diseases in the central nervous system, low survival and inefficient differentiation have restricted its clinical applications. Recently, 3D cell culture methods, such as stem cell–based spheroids and organoids, have demonstrated advantages by incorporating tissue-mimetic 3D cell-cell interactions. However, a lack of drug and nutrient diffusion, insufficient cell-matrix interactions, and tedious fabrication procedures have compromised their therapeutic effects in vivo. To address these issues, we developed a biodegradable nanomaterial-templated 3D cell assembly method that enables the formation of hybrid stem cell spheroids with deep drug delivery capabilities and homogeneous incorporation of 3D cell-matrix interactions. Hence, high survival rates, controlled differentiation, and functional recovery were demonstrated in a spinal cord injury animal model. Overall, our hybrid stem cell spheroids represent a substantial development of material-facilitated 3D cell culture systems and can pave the way for stem cell–based treatment of CNS injuries.