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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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Rationally Designed Zwitterionic Peptides Improve siRNA Delivery of Cationic Diblock Copolymer-Based Nanoparticle Drug-Delivery Systems
Nanoparticle drug-delivery systems (NP DDS) have proven to be tremendously impactful for delivering therapeutic agents in cancer treatments, vaccinations, gene therapy, and diagnostics, and enabled agents such as RNA therapeutics. However, the exposure of NP DDS to biological milieus leads to the rapid adsorption of proteins and other molecules, forming a proteinaceous corona that obscures NP surface characteristics and controls the biological interactions of the NP DDS. Surface modifications, including poly(ethylene glycol) (PEG) and synthetic zwitterionic polymers, reduce protein adsorption yet lack monomer-scale tunability, have off-target immunological effects, and suffer from targeting-limited steric hindrance, altogether motivating the development of alternative approaches. Peptides can uniquely form many zwitterions and have shown promise in reducing and controlling the NP protein corona as a function of the peptide sequence. However, the impact of zwitterionic peptides (ZIPs) on the drug-delivery properties of polymeric NPs has not been explored. In this work, diverse ZIPs computationally predicted to reduce protein adsorption by assessing peptide–peptide β-strand interaction energies were conjugated to pH-responsive cationic NPs. The resulting ZIP-NP conjugates exhibited up to 88% reduced protein adsorption and a range of siRNA-mediated gene knockdown that correlates with interaction energies. These data suggest that the peptide–peptide interaction energy is a promising design parameter for ZIPs for further model development. ZIP-NP also exhibited sequence-dependent variations in cellular uptake and circulation half-life, indicating that ZIP-NPs are suitable for tuning and improving NP drug-delivery characteristics.
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- Award ID(s):
- 2325340
- PAR ID:
- 10586234
- Publisher / Repository:
- ACS Publications
- Date Published:
- Journal Name:
- ACS Applied Nano Materials
- Volume:
- 7
- Issue:
- 13
- ISSN:
- 2574-0970
- Page Range / eLocation ID:
- 15193 to 15206
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1021/acsanm.4c01995
