Engineered Magneto-Piezoelectric Nanoparticles-Enhanced Scaffolds Disrupt Biofilms and Activate Oxidative Phosphorylation in Icam1+ Macrophages for Infectious Bone Defect Regeneration

Abstract

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.

Keywords: Icam1+ macrophages; antibacterial; bone regeneration; infectious bone defects; magneto-piezoelectric; oxidative phosphorylation.