Exosomes, nanoscale extracellular vesicles, play a crucial role in intercellular communication, owing to their biologically active cargoes such as RNAs and proteins. In recent years, they have emerged as a promising tool in the field of tissue regeneration, with the potential to initiate a new trend in cell-free therapy. However, it's worth noting that not all types of exosomes derived from cells are appropriate for tissue repair. Thus, selecting suitable cell sources is critical to ensure their efficacy in specific tissue regeneration processes. Current therapeutic applications of exosomes also encounter several limitations, including low-specific content for targeted diseases, non-tissue-specific targeting, and short retention time due to rapid clearance in vivo. Consequently, this review paper focuses on exosomes from diverse cell sources with functions specific to tissue regeneration. It also highlights the latest engineering strategies developed to overcome the functional limitations of natural exosomes. These strategies encompass the loading of specific therapeutic contents into exosomes, the endowment of tissue-specific targeting capability on the exosome surface, and the incorporation of biomaterials to extend the in vivo retention time of exosomes in a controlled-release manner. Collectively, these innovative approaches aim to synergistically enhance the therapeutic effects of natural exosomes, optimizing exosome-based cell-free strategies to boost endogenous cell functions in tissue regeneration. STATEMENT OF SIGNIFICANCE: Exosome-based cell-free therapy has recently emerged as a promising tool for tissue regeneration. This review highlights the characteristics and functions of exosomes from different sources that can facilitate tissue repair and their contributions to the regeneration process. To address the functional limitations of natural exosomes in therapeutic applications, this review provides an in-depth understanding of the latest engineering strategies. These strategies include optimizing exosomal contents, endowing tissue-specific targeting capability on the exosome surface, and incorporating biomaterials to extend the in vivo retention time of exosomes in a controlled-release manner. This review aims to explore and discuss innovative approaches that can synergistically improve endogenous cell functions in advanced exosome-based cell-free therapies for a broad range of tissue regeneration.