A Nanomedicine Strategy: Spatiotemporally Programmed Delivery of Engineered Exosomes via Smart Scaffolds for Craniofacial Bone Regeneration

Qian Yang,1 Guangmei Ran,1 Hongrui Jin,1 Wentao Zhai,1 Jun Lu,1 Wenjie Jiang,1 Jingjing Luo,2 Shichang Fang,2 Yinchang Zhang,3 Huan Liu,4 Jiating Lin2 1Graduate School of Stomatology, Wannan Medical University, Wuhu, Anhui, 241000, People’s Republic of China; 2Department of Stomatology, Yijishan Hospital, Wannan Medical University, Wuhu, Anhui, 241000, People’s Republic of China; 3Department of Joint Orthopedics, Yijishan Hospital, Wannan Medical University, Wuhu, Anhui, 241000, People’s Republic of China; 4Blood Purification Center, Yijishan Hospital, Wannan Medical University, Wuhu, Anhui, 241000, People’s Republic of ChinaCorrespondence: Jiating Lin, Department of Stomatology, Yijishan Hospital, Wannan Medical University, Wuhu, Anhui, 241000, People’s Republic of China, Tel/Fax +86-553-5739201, Email [email protected]: The convergence of nanomedicine and regenerative biology offers new paradigms for tissue repair. The reconstruction of critical-sized bone defects, particularly within the anatomically intricate and physiologically distinct landscape of the craniomaxillofacial (CMF) region, represents a formidable frontier in regenerative medicine. Bone regeneration is not a singular biological event but a temporally orchestrated symphony, necessitating the precise, sequential coordination of immunomodulation, angiogenesis, and osteogenesis. While mesenchymal stem cell-derived extracellular vesicles (MSC-Exos) have emerged as a paradigm-shifting cell-free therapeutic - circumventing the engraftment instability, tumorigenicity, and immunogenicity limitations of live cell therapies-their clinical translation remains hindered by a fundamental kinetic mismatch: the delivery of a static, unmodulated bolus to a highly dynamic wound microenvironment. Current therapeutic strategies predominantly rely on simple injection or bulk incorporation of MSC-Exos into scaffolds. These static delivery paradigms fail to recapitulate the physiological rhythm of healing, often creating a kinetic mismatch between a single therapeutic cargo and the host’s changing needs. This review bridges a critical synthesis gap by proposing a novel “spatiotemporal programming” framework for bone regeneration. We systematically integrate cargo engineering strategies (eg, hypoxic/inflammatory priming, genetic modification) with smart biomaterial design (eg, stimuli-responsive hydrogels, core-shell scaffolds) to achieve sequential, phase-specific delivery. By aligning exosomal bioactivity with the intrinsic immuno-angiogenic-osteogenic cascade and emphasizing cargo tailoring for craniomaxillofacial specificity, this work provides a translational roadmap for next-generation, precision-guided skeletal reconstruction.Keywords: nanomedicine, mesenchymal stem cell, exosomes, spatiotemporal delivery, bone regeneration