Abstract
Exosomes are nano-sized extracellular vesicles that play a central role in intercellular communication by transferring bioactive proteins, lipids, and nucleic acids to recipient cells. In recent years, exosomes have emerged as promising cell-free therapeutic agents in regenerative medicine due to their ability to modulate inflammation, promote angiogenesis, and stimulate tissue repair. However, the clinical application of exosome-based therapies is limited by rapid clearance, poor retention at target sites, and uncontrolled biodistribution following direct administration. To address these challenges, hybrid regenerative platforms integrating exosomes with three-dimensional biomaterials, particularly natural hydrogels, have gained increasing attention. Natural polymer hydrogels derived from extracellular matrix components, such as collagen, gelatin, hyaluronic acid, alginate, and chitosan, provide a biocompatible and biomimetic microenvironment for exosome delivery. These hydrogels can encapsulate exosomes through physical entrapment or chemical/affinity interactions, offering protection and enabling sustained, localized release. By tuning hydrogel properties – including crosslinking density, porosity, and degradation rate – exosome release kinetics can be precisely controlled. Moreover, stimuli-responsive hydrogels allow on-demand exosome release in response to environmental cues such as pH, temperature, enzymatic activity, or oxidative stress, further enhancing therapeutic precision. Preclinical studies have demonstrated the effectiveness of exosome-infused hydrogels in tissue engineering applications, particularly in bone regeneration, cartilage repair, and skin wound healing, where they enhance tissue integration, vascularization, and functional recovery. Despite these encouraging outcomes, clinical translation remains challenging due to issues related to scalable exosome production, product standardization, long-term safety, and regulatory classification of combination products. This mini-review summarizes current design strategies, release mechanisms, and regenerative applications of exosome–hydrogel systems, and discusses key barriers and future directions for their clinical implementation.