Wu Hao, Chen Changcheng, Li Jiangfeng, Yu Dongmei, Wu Xun, Huang Hai, Tang Zhen, Wu Qi, Yan Shichao, Wang Ning, Wang Mo, Wei Feilong, Yu Yunlong, Wang Duan, Shi Mengting, Yue Xusong, Cao Pengfei, Zheng Zenghui, Li Xiaokang, Guo Baolin, Shi Lei, Guo Zheng
Department of Orthopaedics, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P. R. China.
Institute of Burn Research, Southwest Hospital & State key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University (Army Medical University), Chongqing 400038, P. R. China.
ACS Nano. 2024 Dec 31;18(52):35575-35594. doi: 10.1021/acsnano.4c13562. Epub 2024 Dec 17.
Infectious bone defects pose significant clinical challenges due to persistent infection and impaired bone healing. Icam1 macrophages were identified as crucial and previously unrecognized regulators in the repair of bone defects, where impaired oxidative phosphorylation within this macrophage subset represents a significant barrier to effective bone regeneration. To address this challenge, dual-responsive iron-doped barium titanate (BFTO) nanoparticles were synthesized with magnetic and ultrasonic properties. These nanoparticles were further loaded with the anti-inflammatory agent curcumin and coated with engineered mesenchymal stem cell membranes (EMM) modified with γ3 peptide, creating BFTO-Cur@EMM nanoparticles specifically designed to target Icam1 macrophages. These nanoparticles were shown to disrupt bacterial biofilms under alternating magnetic fields (AMF) and to activate oxidative phosphorylation and osteogenic immune responses in Icam1+ macrophages via low-intensity pulsed ultrasound (LIPUS). Transcriptomic sequencing and validation experiments demonstrated that this approach activates oxidative phosphorylation (OXPHOS) by stimulating the JAK2-STAT3 pathway and inhibiting the MAPK-JNK pathway, thereby promoting the polarization of Icam1+ macrophages toward a pro-reparative phenotype and enhancing the secretion of pro-angiogenic and osteogenic cytokines. These nanoparticles were subsequently integrated into quaternized chitosan (QCS) and tricalcium phosphate (TCP) to create a bioink for three-dimensional (3D) printing anti-infection QT/BFTO-Cur@EMM bone repair scaffolds. In vivo studies indicated that these scaffolds significantly improved the healing of infectious bone defects without causing thermal damage to surrounding tissues. This work highlights the potential of this material and the targeting of Icam1 macrophages as an effective strategy for simultaneously controlling infection and promoting bone regeneration.
感染性骨缺损由于持续感染和骨愈合受损而带来重大临床挑战。Icam1巨噬细胞被确定为骨缺损修复中关键且此前未被认识的调节因子，该巨噬细胞亚群内氧化磷酸化受损是有效骨再生的重大障碍。为应对这一挑战，合成了具有磁性和超声特性的双响应铁掺杂钛酸钡（BFTO）纳米颗粒。这些纳米颗粒进一步负载抗炎剂姜黄素，并包覆用γ3肽修饰的工程化间充质干细胞膜（EMM），从而制备出专门靶向Icam1巨噬细胞的BFTO-Cur@EMM纳米颗粒。这些纳米颗粒在交变磁场（AMF）下可破坏细菌生物膜，并通过低强度脉冲超声（LIPUS）激活Icam1+巨噬细胞中的氧化磷酸化和成骨免疫反应。转录组测序和验证实验表明，该方法通过刺激JAK2-STAT3途径和抑制MAPK-JNK途径来激活氧化磷酸化（OXPHOS），从而促进Icam1+巨噬细胞向促修复表型极化，并增强促血管生成和成骨细胞因子的分泌。随后将这些纳米颗粒整合到季铵化壳聚糖（QCS）和磷酸三钙（TCP）中，制备出用于3D打印抗感染QT/BFTO-Cur@EMM骨修复支架的生物墨水。体内研究表明，这些支架显著改善了感染性骨缺损的愈合，且不会对周围组织造成热损伤。这项工作突出了这种材料的潜力以及靶向Icam1巨噬细胞作为同时控制感染和促进骨再生的有效策略。
