Maintaining both cell–cell and cell–extracellular matrix (ECM) interactions is often a critical component of 3D tissue regeneration. In high‐density cell condensation systems, lack of appropriate cell–ECM interactions can result in limited and/or slow cell differentiation and tissue formation. To address these problems, a colloidosome microsphere system that is composed of a gelatin hydrogel core and a porous nanoparticle shell is developed. The colloidosome microsphere functions as an ECM and morphogen carrier for the induction of cartilage formation of high‐density human mesenchymal stem cell (hMSC) in 3D cultures. With the protection of the nanoparticle shell, the colloidosome microspheres can be readily suspended in aqueous solution without clumping, thus incorporated homogeneously within high‐density cell condensations. The gelatin‐based colloidosome microspheres stimulate chondrogenesis of hMSCs and degrade rapidly to facilitate ECM remodeling for new tissue formation. When loaded with human transforming growth factor‐β1, a potent chondrogenic morphogen, the colloidosomes serve as a bioactive factor delivery vehicle as well. The dual functionality of the colloidosomes as an ECM and a growth factor carrier effectively supports the chondrogenic differentiation of high‐density hMSC condensations. These capabilities render the colloidosomes a promising platform system amenable to large‐scale production of high‐density 3D tissue culture constructs.

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