Nanofibrillated cellulose has long been studied as a bioactive material in tissue engineering; however, the mechanism of surface chemistry-mediated immune reprogramming remains unclear. This paper reports a comprehensive multi-omics study of pure cellulose nanocrystals (CNCs) and amide-functionalized CNCs (a-CNCs), aiming to elucidate their "nano-immune" interactions in vivo and their effects on resident macrophages in tissues. Through integrated scRNA-Seq, whole RNA-Seq, pharmacological inhibition, and histological analysis, we found that a-CNCs exhibited excellent biocompatibility, and in the 14-day subacute window, macrophages in major organs did not show pro-inflammatory activation. Specifically, a-CNC exposure was associated with enhanced voltage-gated ion channels (KCa3.1 and Scn1b) and Stat6 signaling, while inhibiting Nfkb-driven pro-inflammatory signals. This indicates that ion channel activation is closely related to M2 macrophage polarization. Additionally, the 28-day spleen cell profiling analysis showed no significant increase in CD4+/CD8+ T cells, suggesting an absence of adaptive immune response after exposure to a-CNCs. Moreover, pseudo-time localization further indicated that a-CNC exposure could preserve the natural macrophage development trajectory of the organ niche, while pure CNCs would induce a mild M1 shift in the spleen. In vitro verification confirmed that a-CNCs essentially drive a healing-promoting phenotype in macrophages, emphasizing that macroscopic immune behavior can be triggered by the nanoscale surface chemistry reaction of CNCs.
This study was published in Bioactive Materials under the title "Ion channel/Stat6-driven nano-immune programming of tissue-resident macrophages by amide-functionalized nanocellulose". References:
DOI: 10.1016/j.bioactmat.2026.03.038