Updated project metadata. Lipid nanoparticles (LNPs) play a crucial role in addressing genetic disorders, and cancer, and combating pandemics such as COVID-19 and its variants. Yet, in contrast remarkable achievements in siRNA and mRNA delivery, the ability of LNPs to effectively encapsulate large-size DNA molecules remains elusive. This is a significant limitation, as the successful delivery of large-size DNA holds immense potential for gene therapy, offering transformative opportunities for the treatment of a wide range of genetic diseases. To address this gap, the present study focuses on the design of PEGylated LNPs, incorporating large-sized DNA, and cationic lipids departing from traditional RNA and ionizable lipids. The resultant LNPs demonstrate a unique particle morphology characterized by distinct layered subunits composed of alternating lipid bilayers and DNA monolayers. Inspired by the ability of DNA to neutralize cationic lipids and promote the formation of an opsonin-deficient protein corona, these particles were further engineered after initial synthesis with a DNA coating and plasma proteins. This novel multicomponent bionanoconstruct exhibits enhanced transfection efficiency and safety in controlled laboratory settings and improved immune system evasion in in vivo tests. This capacity is attributed to its superior ability to evade lysosomal degradation and immune cell capture, a phenomenon that is mediated by a complex interplay among PEGylation, the protein corona, and DNA within the structure. These findings provide valuable insights for the design and development of bionanoarchitectures for large-size DNA delivery, opening new avenues for transformative gene therapies