Self‐Assembled Nanoclay Gel With Spheroid MSC‐Derived Exosome Mimetics to Integrate Demineralized Bone Matrix and Noggin‐Targeting miRNA for Synergistic Osteogenesis

ABSTRACT Demineralized bone matrix (DBM) is widely used as an alternative to autografts for repairing bone defects, but its clinical efficacy is limited by poor retention at the defect site and inadequate osteogenic capacity. Here, we developed a multifunctional carrier system aimed at improving the capacity of DBM by utilizing nanoclay‐based self‐assembly along with cell‐derived exosome mimetics (EMs). EMs were derived from mesenchymal stem cells (MSCs) osteogenically induced in spheroids and were functionalized with bisphosphonates (BP) to assemble a stable gel network with laponite nanoclays via BP‐nanoclay edge interactions. The resulting self‐assembled nanoclay gel exhibited excellent injectability, moldability, and self‐healing properties, even when loaded with a high concentration of DBM, and supported MSC osteogenic differentiation. We further enhanced the potency of DBM‐mediated osteogenesis and bone morphogenetic protein (BMP) signaling in the nanoclay gel by incorporating BP‐functionalized EMs (EM‐BPs) loaded with miR‐200c that can target BMP antagonist noggin. Lastly, we validated the bone regeneration efficacy of DBM‐loaded nanoclay gels in comparison to commercially available DBM putties using a mouse calvarial defect model. This approach presents a versatile nanoclay gel carrier platform that overcomes the limitations of current DBM formulations and provides a promising strategy for improved bone repair.