Despite decades of progress, developing minimally invasive bone‐specific drug delivery systems (DDS) to improve fracture healing remains a significant clinical challenge. To address this critical therapeutic need, nanoparticle (NP) DDS comprised of poly(styrene‐alt‐maleic anhydride)‐b‐poly(styrene) (PSMA‐b‐PS) functionalized with a peptide that targets tartrate‐resistant acid phosphatase (TRAP) and achieves preferential fracture accumulation has been developed. The delivery of AR28, a glycogen synthase kinase‐3 beta (GSK3β) inhibitor, via the TRAP binding peptide‐NP (TBP‐NP) expedites fracture healing. Interestingly, however, NPs are predominantly taken up by fracture‐associated macrophages rather than cells typically associated with fracture healing. Therefore, the underlying mechanism of healing via TBP‐NP is comprehensively investigated herein. TBP‐NPAR28promotes M2 macrophage polarization and enhances osteogenesis in preosteoblast‐macrophage co‐cultures in vitro. Longitudinal analysis of TBP‐NPAR28‐mediated fracture healing reveals distinct spatial distributions of M2 macrophages, an increased M2/M1 ratio, and upregulation of anti‐inflammatory and downregulated pro‐inflammatory genes compared to controls. This work demonstrates the underlying therapeutic mechanism of bone‐targeted NP DDS, which leverages macrophages as druggable targets and modulates M2 macrophage polarization to enhance fracture healing, highlighting the therapeutic benefit of this approach for fractures and bone‐associated diseases.
The newest generation of drug delivery systems (DDSs) exploits ligands to mediate specific targeting of cells and/or tissues. However, studies investigating the link between ligand density and nanoparticle (NP) uptake are limited to a small number of ligand‐receptor systems. C‐type lectin‐like molecule‐1 (CLL1) is uniquely expressed on myeloid cells, which enables the development of receptors specifically targeting treat various diseases. This study aims to investigate how NPs with different CLL1 targeting peptide density impact cellular uptake. To this end, poly(styrene‐alt‐maleic anhydride)‐
- NSF-PAR ID:
- 10454261
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Advanced Biosystems
- Volume:
- 4
- Issue:
- 11
- ISSN:
- 2366-7478
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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