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Abstract Macrophages are a predominant immune cell population that drive inflammatory responses and exhibit transitions in phenotype and function during tissue remodeling in disease and repair. Thus, engineering an immunomodulatory biomaterial has significant implications for resolving inflammation. Here, a biomimetic and photoresponsive hyaluronan (HA) hydrogel nanocomposite with tunable 3D extracellular matrix (ECM) adhesion sites for dynamic macrophage immunomodulation is engineered. Photodegradative alkoxylphenacyl‐based polycarbonate (APP) nanocomposites are exploited to permit user‐controlled Arg–Gly–Asp (RGD) adhesive peptide release and conjugation to a HA‐based ECM for real‐time integrin activation of macrophages encapsulated in 3D HA–APP nanocomposite hydrogels. It is demonstrated that photocontrolled 3D ECM–RGD peptide conjugation can activate αvβ3 integrin of macrophages, and periodic αvβ3 integrin activation can enhance anti‐inflammatory M2 macrophage polarization. Altogether, an emerging use of biomimetic, photoresponsive, and bioactive HA–APP nanocomposite hydrogel is highlighted to command 3D cell–ECM interactions for modulating macrophage polarization, which may shed light on cell–ECM interactions in innate immunity and inspire new biomaterial‐based immunomodulatory therapies.
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Bone‐Targeted Nanoparticle Drug Delivery System‐Mediated Macrophage Modulation for Enhanced Fracture Healing
Abstract 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.
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- Award ID(s):
- 2325340
- PAR ID:
- 10467970
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Small
- ISSN:
- 1613-6810
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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