Recent advances in biomaterials have revealed the importance of material-biology interplay, which is termed as “materiobiology” to describe the regulatory effects of biomaterial properties on biological functions at cell, tissue, organ, and the whole organism levels. A typical example of materiobiology is material-induced host immune response, the earliest biological behavior after material implantation in vivo, which plays a determinant role in material application, especially for tissue engineering/regeneration. It is therefore necessary to dissect the cellular and biochemical mechanisms under material-immune cell interaction, which will facilitate the design/development of biomaterials with the capacity to induce an ideal immune environment for tissue regeneration. In the current study, we found that dihydrolipoic acid-gold nanoclusters (AuNCs), a type of fluorescent materials for biolabelling and bioimaging, effectively regulated macrophage inflammatory response. AuNCs made up of 10 to 100 atoms have ultra-small size (< 3 nm) and therefore could efficiently accumulate in macrophages. The results showed that under inflammatory stimulation, AuNC-uptake effectively suppressed macrophage response by inducing the phenotype switch from inflammatory M1 towards tissue-regenerative M2 in a dose-dependent manner, which was achieved through activation of autophagy in inflammatory macrophage. The activated autophagy facilitated the clearance of damaged mitochondria (termed as mitophagy), an effect not only preventing intracellular accumulation of reactive oxygen species (ROS), but also shifting the energy metabolism pattern from glycolysis into oxidative phosphorylation (mitochondria-dependent). This reprogramed macrophage response was found to facilitate both osteogenic differentiation and bone regeneration in vitro and in vivo, suggesting that AuNC-application could generate a favourable immune microenvironment for tissue regeneration. Therefore, our study has discovered a novel mechanism under nanomaterial-induced immunomodulation on macrophage response, which also provides a potential approach for translational tissue regeneration in the future.