Exosome-loaded hydrogels for bone regeneration: a cell-free therapeutic strategy

Abstract Bone defects present significant challenges in clinical practice due to the limitations of traditional treatments. Compared to traditional cell therapies, exosome-based therapies have emerged as a promising alternative, offering a cell-free therapeutic strategy that harnesses the regenerative potential of stem cells. Exosome-based therapies are without the risks associated with live cell therapies, such as immune rejection and the complexities of large-scale cell culture systems. However, challenges such as stability and targeted delivery remain in the clinical translation of exosome therapies. To address these, recent advancements have focused on exosome-loaded hydrogels, which provide a controlled release system for exosomes, protecting them from degradation and ensuring sustained therapeutic effects at the bone defect site. These hydrogel systems offer an ideal environment for cell attachment, migration, and tissue formation, enhancing bone healing. This review explores exosomes in bone tissue engineering derived from mesenchymal stem cells (MSCs), adipose-derived stem cells (ADSCs), and other resources such as dental pulp stem cells (DPSCs), urine derived stem cells (USCs), and even skeletal stem cells (SSCs). Moreover, innovative strategies have been used to enhance the efficacy of exosome-based therapies, such as exosome mimetics‑loaded hydrogels as a scalable cell‑free strategy and “armored exosomes” as protective exosome formulations in functional hydrogels. There are challenges in clinical application, such as standardization of exosome production, long-term stability, immune response, and regulatory approval. Exosome-loaded hydrogels offer a scalable, effective, and safe alternative to traditional cell-based therapies in bone regeneration.