Bone-Targeted Nanoparticles to Accelerate Fracture Healing in Aging Populations

Project Summary/Abstract Fractures significantly contribute to morbidity and mortality worldwide, particularly among aging populations. In the US alone, over 15 million fractures occur annually, with approximately 10% leading to complications such as delayed unions or nonunions. Despite these staggering statistics, no non-surgical therapies are available to address impaired fracture healing, leaving patients susceptible to prolonged disability, increased healthcare costs, and a heightened risk of mortality. This proposal aims leverages our nanoparticle-based therapeutic that modulates the regenerative microenvironment at fracture sites. The delivery system targets tartrate-resistant acid phosphatase (TRAP) as a biomarker to guide nanoparticles to fracture sites. These nanoparticles, functionalized with the TRAP-binding peptide (TBP) and loaded with the Wnt/β-catenin pathway agonist AR28, provide the dual benefit of targeted delivery and therapeutic modulation. Preliminary data show that TBP- NPAR28 accumulates preferentially at fracture sites in young-adult mice, accelerating healing as evidenced by biomechanical, histological, and radiographic analyses. TBP-NPAR28 was found to be mainly internalized by MФs at the fracture site rather than directly targeting osteogenic cells such as mesenchymal stem cells (MSCs) or osteoblasts. This finding represents a paradigm shift in regenerative medicine: rather than directly stimulating osteogenic cells, TBP-NPAR28 leverages MФs as master regulators of the healing microenvironment. By leveraging the unique biology of MФs and their vital role in orchestrating the transitions between the inflammatory, proliferative, and remodeling stages of healing, this approach tackles aberrant MФ function—a newly identified barrier to successful fracture repair in aging individuals. By reprogramming MФ phenotypes to facilitate timely and effective transitions from pro-inflammatory (M1) to pro-regenerative (M2) states, TBP-NPAR28 addresses a fundamental mechanism underlying impaired fracture healing in aging populations. The proposed UG3/UH3 program will rigorously assess the safety, efficacy, and therapeutic mechanisms of TBP-NPAR28, laying the groundwork for the clinical translation of this first-in-class therapeutic. The UG3 phase will prioritize evaluating TBP-NPAR28’s safety and fracture-regenerative efficacy in aged mice and rats, utilizing robust preclinical models to identify optimal dosing, timing, and safety profiles. The UH3 phase will build upon this foundation, optimizing nanoparticle delivery parameters, clarifying therapeutic mechanisms, and conducting IND-enabling studies to ensure regulatory compliance and readiness for clinical trials. By targeting the regenerative microenvironment through macrophage modulation, TBP-NPAR28 represents a transformative therapeutic strategy with the potential to enhance fracture healing outcomes in aging populations. Moreover, the TBP-NP platform offers broad utility for targeting other disease states where macrophage dysfunction contributes to pathology, paving the way for future innovations in nanoparticle-based regenerative medicine.