Injectable microsphere-based delivery strategies for stem cells and their derivatives in tissue regeneration

Tissue and organ injury, degeneration, and functional loss represent a growing global health challenge, exacerbated by an aging population and the limitations of current clinical interventions. Regenerative medicine offers a promising alternative by restoring tissue function through the delivery of stem cells and their bioactive derivatives, particularly exosomes. However, direct administration of these therapeutic agents faces significant hurdles, including low retention, rapid clearance, and poor spatiotemporal control. Injectable microsphere-based delivery systems have emerged as a versatile and minimally invasive platform to overcome these limitations. This review systematically outlines the latest advances in microsphere-mediated strategies for delivering stem cells and their derivatives across multiple tissue types, including bone, cartilage, neural, skin, dental pulp, cardiac and lung. We critically evaluate the design principles of natural and synthetic polymers, fabrication techniques such as microfluidics and electrospray, and the biological functions of microspheres in providing three-dimensional (3D) scaffolds, immune protection, and sustained release. Furthermore, we highlight emerging frontiers, including the delivery of novel regenerative cues such as apoptotic bodies and the integration of microsphere-based organoid models. This comprehensive analysis aims to accelerate the clinical translation of next-generation microsphere-enabled regenerative therapies.