Nanocellulose has long been studied as a bioactive material for tissue engineering; however, the mechanisms underlying its surface chemistry-mediated immune reprogramming remain unclear. Herein, we report a comprehensive multi-omics study of pristine cellulose nanocrystals (CNCs) and amide-functionalized CNCs (a-CNCs) to elucidate their 'nano-immune' interaction and impact on tissue-resident macrophages in vivo. Using integrated scRNA-Seq, bulk RNA-Seq, pharmacological inhibition, and histological profiling, we reveal that a-CNCs exhibit outstanding biocompatibility, showing no pro-inflammatory activation of macrophages across major organs within 14-day subacute window. In particular, a-CNCs exposure correlates with enhanced voltage-gated ion channel (KCa3.1 and Scn1b) and Stat6 signaling, while suppressing Nfkb-driven pro-inflammatory signals. This suggest that ion channel activation is strongly associated with M2 macrophage polarization. Moreover, a 28-day splenocytes profiling revealed no observable increase in CD4⁺/CD8⁺ T cells, suggesting non-adaptive immune response after a-CNC exposure. Concurrently, pseudotime mapping further discloses that a-CNC exposure preserves natural macrophage developmental trajectories across organ niches, while pristine CNCs induce mild M1-skewing in the spleen. In vitro validation confirms that a-CNCs intrinsically drive a pro-healing phenotype in macrophages, underscoring that macro-scale immune behavior can be transcriptionally triggered through nano-level surface chemistry of CNCs.