Ultra-Tiny Gelatin Nanoparticles-Assisted 3D Stem Cell Spheroids for Engineering Tissue Regeneration.

Stem cell spheroids offer an effective approach for tissue repair, disease modeling, and therapeutic applications. However, traditional spheroid cultures face certain limitations, such as uncontrolled cell proliferation and size, lack of structural complexity, and limited nutrient diffusion, eventually causing core apoptosis. Therefore, this study aims to propose an ultra-tiny gelatin nanoparticle (GNP)-assisted spheroid culture system designed to promote compact spheroid formation and enhance intra-/intercellular functionality. Highly biocompatible GNPs (80-150 nm) are fabricated with unique properties that promote cell-cell and cell-extracellular matrix (ECM) interactions, thereby enhancing functionality in stem cell spheroids. Compared to traditional stem cell spheroid culture methods, GNP-stem cell spheroids show improved cell viability, proliferation, and cellular complexity. Furthermore, the time-dependent regenerative potential of fabricated GNP-stem cell spheroids is investigated in hard and soft tissue defect sites. These findings indicate the significant role of GNP-stem cell spheroids in accelerating bone and skin tissue regeneration. These groundbreaking findings establish GNP-enhanced spheroids as a transformative innovation in regenerative medicine, surpassing traditional 3D stem cell therapies and advancing tissue engineering and biomedical research.