Bone-Derived Nanoparticles for Targeted rhBMP2 Delivery to Restore Function and Promote Osteogenic Differentiation in Radiation-Damaged Bone Marrow Stem Cells

About This Grant

PROJECT SUMMARY High-dose ionizing radiation (IR), whether from radiotherapy, environmental exposure, or space travel, causes profound and lasting skeletal damage by disrupting bone remodeling through DNA damage, oxidative stress, and vascular compromise, leading to accelerated bone loss, delayed healing, increased fracture risk, and osteoradionecrosis. IR also alters the bone marrow microenvironment, severely impairing bone marrow-derived mesenchymal stem cells (BMSCs), key drivers of bone regeneration, by reducing their proliferation, inducing senescence, and shifting their differentiation from osteogenesis to adipogenesis. Current clinical treatments provide only temporary relief and do not address the underlying cellular damage. Therefore, it is essential to develop strategies that protect BMSCs from IR-induced injury and restore their osteogenic potential to preserve bone architecture and support long-term bone regeneration in IR-related skeletal injuries. Nanomedicine offers transformative opportunities to address IR-induced bone damage by enabling targeted delivery of therapeutic agents at nanoscale. To this end, our laboratory has developed an innovative class of bone-derived nanoparticles (BPs) synthesized from decellularized bone matrix. These BPs offer several advantages, including nanoscale size for efficient cellular uptake, excellent biocompatibility, and a natural bone composition that supports bone regeneration. Our preliminary studies demonstrated that BPs alone can partially mitigate IR-induced cellular damage in BMSCs by restoring critical pathways such as cell cycle progression, DNA repair, and RNA processing. While BPs improved BMSC survival and function following IR exposure, they did not fully restore osteogenic differentiation. To enhance their therapeutic potential, we developed a second- generation system by encapsulating recombinant human Bone Morphogenetic Protein 2 (rhBMP2) within the BPs (termed rhBMP2/BPs). Using tunable crosslinking, we achieved sustained and controlled release of bioactive rhBMP2, creating a platform that significantly enhances osteogenesis in IR-damaged BMSCs by combining the protective properties of bone-derived matrix with osteoinductive effects of rhBMP2. We hypothesize that rhBMP2/BPs will function as a dual-action nanotherapeutic targeting the bone marrow niche to (1) mitigate IR-induced cellular damage by delivering bone-derived matrix proteins that restore key regenerative pathways such as proliferation, DNA repair, and cell cycle progression, and (2) promote sustained osteogenesis through controlled intracellular release of rhBMP2. This prolonged bioactivity is expected to enhance bone structure, restore mechanical strength, and support long-term regeneration. The ultimate goal is to develop and validate rhBMP2/BPs as a bone marrow-targeted therapy that restores BMSC function and promotes effective repair and regeneration of irradiated segmental bone defects, supported by mechanistic in vitro analyses and therapeutic evaluation in clinically relevant animal models. This dual-action approach highlights the translational potential of rhBMP2/BPs for treating IR-related skeletal complications.