Targeted Delivery of NGF-Pretreated Schwann Cell-Derived Exosomes for Osteoporosis Therapy: Overcoming Pain while Enhancing Bone Formation

Abstract Osteoporosis (OP) is a prevalent skeletal disorder characterized by decreased bone mass and increased fragility, leading to fractures and chronic pain. Nerve growth factor (NGF) plays a pivotal role in bone homeostasis and neuro-regeneration but paradoxically exacerbates pain. This study investigated the therapeutic potential of engineered, bone-targeting exosomes derived from NGF-pretreated Schwann cells (NGF-Exo-Pep) for the treatment of OP. We demonstrated that NGF-Exo-Pep effectively promoted osteogenic differentiation and mineralization of bone marrow mesenchymal stem cells (BMSCs) in vitro, while also enhancing Schwann cell proliferation, migration, and neurotrophic factor secretion. Mechanistically, miRNA sequencing revealed that NGF-Exo-Pep was enriched in osteogenic miRNAs. In vivo, NGF-Exo-Pep treatment in ovariectomized mice significantly improved bone microarchitecture, increased osteoblast activity, reduced osteoclast activity, and neurotization of bone tissue. Notably, NGF-Exo-Pep alleviated pain-related behaviors by downregulating pain mediators and reducing c-Fos expression in the spinal cord. This study presented a novel and promising strategy for OP treatment, harnessing the pro-regenerative properties of NGF while mitigating its pain-inducing side effects.