Successful delivery of gene-editing tools using nano-systems is dependent on the ability of nanoparticles (NPs) to pass through the cellular membrane. After internalization by phagocytes, NPs are taken up in vesicular phagolysosomes. Phagosomal leakage, redox imbalance and ionic movements induced by toxic NPs result in inflammation. Although their effects in the cytoplasm are limited to targeting circular ribonucleic acids, they have drastic impact on the epigenome. While NPs induce immunotoxicity by affecting immune-specific signaling pathways, they exhibit genotoxic action. NP-induced immunotoxicity and genotoxicity partly share the same metabolic pathways. Following the internalization to the nucleus, NPs participate in chromatin remodeling, thus, epigenetic landscape changes by inducing DNA methylation changes, modifications of histone proteins, and noncoding RNA expression. The metabolic and epigenetic reprogramming involving the development of innate memory are strictly linked. DNA methyltransferases (DNMTs) can induce transcriptional repression by methylating cytosines (m5C) in Cystidine-Guanine dinucleotide-rich sequences. DNMTs can bind and be regulated by long noncoding RNAs. Epigenetic mechanisms play vital roles not only in the activation, differentiation and effector function(s) of immune cells, but also in cancer initiation and progression via epigenetic alterations related to the multiple oncogenic or tumor suppressor gene pathways.