Lei Jin

The collapse of endogenous bone-regenerative capacity originates from a hostile niche, cellular dysfunction and an insufficient energy supply. To tackle these problems systematically, we have developed a hierarchically organized, mutually reinforcing engineering platform that centers on mesenchymal stem cells (MSCs) and their extracellular vesicles (EVs). First, we rebuilt the stem-cell niche to optimize functional output. A 3-D nano-zirconia scaffold that mimics cancellous bone was seeded with dental-pulp MSCs, faithfully recapitulating the physiological microenvironment. EVs harvested from this 3-D culture (3D-EVs) far outperformed conventional 2D-EVs in resolving inflammatory milieus and driving osteogenic differentiation, confirming that “niche determines vesicle function.” Armed with these function-enhanced EVs, we next sought the fundamental energy driver of regeneration. We therefore encapsulated plant chloroplasts inside MSC membranes, creating “thylakoid-like” particles that could be internalized by MSCs. Acting as intracellular “bio-generators,” these particles raise local ATP levels upon light exposure, directly “charging” the energy-intensive process of osteogenesis and thereby amplifying MSC potency from a metabolic perspective. Inspired by traditional Chinese medicine and our intracellular thylakoids, we next turned to plant-derived exosomes to reprogram the host immune environment. A composite gel loaded with Calendula officinalis exosomes was found to steer macrophage polarization, creating a pro-regenerative milieu for MSC-based bone formation in vivo— marking the transition of our strategy from in-vitro engineering to in-vivo niche reprogramming. Finally, by dissecting the recalcitrant disease model of bisphosphonate-related osteonecrosis of the jaw (BRONJ), we validated and extended the core logic of the above pipeline. We showed that BRONJ pathology is intimately linked to MSC failure and identified miR-145 as a serum biomarker. We therefore engineered exosomes enriched in miR-145; these vesicles suppress MSC ferroptosis, enhance osteogenic differentiation and precisely intervene in the disease process. Most importantly, the treatment systemically restored MSC regenerative capacity, reversed osteoporosis and healed critical-size calvarial defects. This not only offers a therapy for BRONJ, but also proves that targeting key molecular circuits in MSCs can shift the endpoint from local necrosis repair to a systemic resurrection of bone-regenerative ability. Collectively, by moving from biomimetic niche construction and metabolic empowerment to immune modulation and, ultimately, disease-model-guided validation, our MSC/EV platform achieves strategic control over systemic bone regeneration, providing a comprehensive bench-to-bedside solution for regenerative medicine.

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