Extracellular vesicles (EVs) are promising tools for cell-free regenerative medicine due to their ability to modulate biological processes. However, rapid clearance and poor targeting limit their efficacy and clinical translation. Recent bioengineering advances have enabled EVs integration with biomaterials to enhance their stability, bioavailability, and controlled release, maximizing their therapeutic potential. This review analyzes the strategies used to interface EVs with biomaterials, including hydrogels, scaffolds, and implantable materials, and discusses their application in tissue engineering and regenerative medicine field. The advantages and limitations of different EVs sources, from tissue-resident cells to stem cells, and EVs immobilization techniques, from physical entrapment to covalent binding, are examined. Challenges in clinical translation are addressed, while proposing potential solutions to accelerate the development of EV-biomaterial hybrids for therapeutic use. The integration of EVs with bioengineered materials represents a paradigm shift, offering innovative solutions for enhancing the innate ability of EVs to promote tissue repair and functional recovery. STATEMENT OF SIGNIFICANCE: Extracellular vesicles (EVs) have emerged as powerful tools for regenerative medicine, yet challenges such as rapid clearance and limited targeting hinder their clinical application. This review explores the integration of EVs with bioengineered materials to enhance their stability, control their release, and maximize therapeutic potential. We provide a comprehensive analysis of state-of-the-art strategies to bridge biomaterials science and EV therapeutics, highlighting their advantages and translational challenges. Furthermore, this review offers a roadmap of the challenges required to overcome for advancing EV-based therapies toward clinical translation.
