Cell therapy (also known as cell transplantation) has been considered promising as a next-generation living-cell therapy strategy to surpass the effects of traditional drugs. However, their practical clinical uses and product conversion are hampered by the unsatisfied viability and efficacy of the transplanted cells. Herein, we propose a synergistic enhancement strategy to address these issues by constructing 3D stem cell spheroids integrated with urchin-like hydroxyapatite microparticles (uHA). Specifically, cell-sized uHA microparticles were synthesized via a simple hydrothermal method using glutamic acid (Glu, E) as the co-template with good biocompatibility and structural antimicrobial performance (denoted as E-uHA). Combining with a hanging drop method, stem cell spheroids integrated with E-uHA were successfully obtained by culturing bone marrow mesenchymal stem cells (BMSCs) with a low concentration of the E-uHA suspensions (10 μg mL-1). The resulting composite spheroids of BMSCs/E-uHA deliver a high cellular viability, migration activity, and a superior osteogenic property compared to the 2D cultured counterpart or other BMSC spheroids. This work provides an effective strategy for integrating a secondary bio-functional component into stem cell spheroids for designing more cell therapy options with boosted cellular viability and therapeutic effect.