Bone-Targeted Nanoparticle Drug Delivery System-Mediated Macrophage Modulation for Enhanced Fracture Healing.
Bone-Targeted Nanoparticle Drug Delivery System-Mediated Macrophage Modulation for Enhanced Fracture Healing.
复制标题
骨靶向纳米颗粒药物递送系统介导的巨噬细胞调节以促进骨折愈合 。
DOI：
10.1002/smll.202305336
复制
发表时间：
2023-10
期刊：
影响因子：
13.3
通讯作者：
Baixue Xiao;Yuxuan Liu;Indika Chandrasiri;Emmanuela Adjei-Sowah;Jared Mereness;Ming Yan;Danielle S W Beno
中科院分区：
文献类型：
--
作者：
Baixue Xiao;Yuxuan Liu;Indika Chandrasiri;Emmanuela Adjei-Sowah;Jared Mereness;Ming Yan;Danielle S W Beno
尽管经过几十年的发展，开发微创骨特异性药物递送系统（DDS）以改善骨折愈合仍然是一个重大的临床挑战。为了解决这一关键的治疗需求，已经开发了由聚（苯乙烯-alt-马来酸酐）-b-聚（苯乙烯）（PSMA-b-PS）组成的纳米颗粒（NP）DDS，该DDS用靶向抗酒石酸酸性磷酸酶（TRAP）并实现优先骨折累积的肽功能化。通过TRAP结合肽-NP（TBP-NP）递送糖原合成酶激酶-3 β（GSK 3 β）抑制剂AR 28加速骨折愈合。然而，有趣的是，NP主要被骨相关巨噬细胞而不是通常与骨折愈合相关的细胞摄取。因此，本文全面研究了通过TBP-NP愈合的潜在机制。TBP-NPAR 28促进M2巨噬细胞极化并增强体外前成骨细胞-巨噬细胞共培养物中的骨生成。TBP-NPAR 28介导的骨折愈合的纵向分析揭示了与对照相比M2巨噬细胞的不同空间分布、增加的M2/M1比率以及抗炎基因的上调和促炎基因的下调。这项工作证明了骨靶向NP DDS的潜在治疗机制，该机制利用巨噬细胞作为可药用靶点，并调节M2巨噬细胞极化以促进骨折愈合，突出了这种方法对骨折和骨相关疾病的治疗益处。
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-NPAR28 promotes 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.