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.

Grant Number: 1UG3AG097136-01
NIH Institute/Center: NIH
Principal Investigator: Danielle Benoit