Orchestrating Tendon Regeneration through Nanoparticle Drug Delivery - Project Summary Tendon regeneration following acute injury is marred by a fibrotic healing response that impairs complete functional recovery. Despite the frequency of injuries and complications associated with poor healing, including re-injury and limited range of motion, no pharmacological approaches exist to improve tendon healing. While several interventions have been proposed, systemic treatments lack tendon specificity, resulting in poor tendon biodistribution and off-target toxicities. We recently made the serendipitous discovery via spatial transcriptomic profiling that inflammatory tissue at the healing tendon site is enriched for expression of Acp5, the gene encoding tartrate-resistant acid phosphatase (TRAP), and our preliminary data show robust TRAP activity in the healing tendon. Therefore, to enable tendon targeting, we have leveraged our TRAP binding peptide (TBP) functionalized nanoparticle (NP) drug delivery system (DDS) comprised of poly(styrene-alt-maleic anhydride)- b-poly(styrene) (PSMA-PS) to successfully target extracellular matrix TRAP deposited in the healing tendon. After accumulation at the tendon, NPs are primarily taken up by macrophages (M), critical regulators of the fibrotic healing response in adult tendons, and the insufficient matrix elaboration phenotype observed in aged tendon healing. As such, we will optimize and leverage our promising TBP-NP system to test the central hypothesis that TBP-NPs can be tuned to enable efficient tendon targeting at various points during healing to enhance tendon regeneration in adult and aged models. We will develop this innovative platform technology and test this hypothesis through three aims: Aim 1. Maximize spatiotemporal tendon targeting and delineate cellular targets of TBP-NPs, Aim 2. Establish the efficacy of TBP-NP drug delivery to promote adult tendon healing; Aim 3. Establish the efficacy of TBP-NP drug delivery to promote aged tendon healing. Successful completion of these studies will establish a novel nanoparticle-mediate delivery system to target the healing tendon with high efficiency and efficacy, which achieves tendon healing by modulating macrophage polarization. In sum, this work will substantially enhance the translational feasibility of non-invasive pharmacotherapies for tendon regeneration.
