Plant Exosome-Loaded Intelligent Hydrogels for Osteoporotic Bone Regeneration: Mechanisms and Applications

Osteoporotic bone defects (OBDs), characterized by disrupted bone metabolic homeostasis, insufficient vascularization, and a persistent inflammatory microenvironment, exhibit poor intrinsic regenerative capacity and remain a pressing clinical challenge in orthopedic practice. Plant-derived exosomes (P-Exos)-a unique class of bioactive nanovesicles enriched in regulatory miRNAs, lipids, proteins, and phytoactive metabolites-have emerged as promising natural modulators capable of enhancing osteogenic differentiation, suppressing excessive osteoclast activity, promoting angiogenesis, and mitigating inflammation. Intelligent hydrogels, with their tunable physicochemical properties, high biocompatibility, and extracellular matrix-mimicking architecture, provide a versatile platform for stabilizing P-Exos and achieving controlled, spatiotemporally regulated release. This review systematically summarizes the biological characteristics of P-Exos and elucidates their roles in orchestrating osteoporotic bone repair. Particular emphasis is placed on the design principles of environmentally responsive hydrogels-including thermosensitive, pH-responsive, photocrosslinkable, and other stimuli-adaptive systems-and their capacity to efficiently encapsulate and precisely deliver P-Exos. Furthermore, the synergistic effects of P-Exos-hydrogel composites in modulating the osteoimmune microenvironment, reinforcing angiogenesis-osteogenesis coupling, and accelerating functional bone regeneration are highlighted. Finally, the review addresses the major challenges that impede clinical translation, including the lack of standardized large-scale production of P-Exos, incomplete pharmacokinetic profiles under hydrogel-mediated release, and limited long-term in vivo data. Overall, this work provides a comprehensive conceptual framework and technical perspective to guide the development of safe, efficient, and precision-engineered therapeutic strategies for the treatment of osteoporotic bone defects.