Evasion of opsonization of macromolecules using novel surface‐modification and biological‐camouflage‐mediated techniques for next‐generation drug delivery

Abstract Opsonization plays a pivotal role in hindering controlled drug release from nanoformulations due to macrophage‐mediated nanoparticle destruction. While first and second‐generation delivery systems, such as lipoplexes (50–150 nm) and quantum dots, hold immense potential in revolutionizing disease treatment through spatiotemporal controlled drug delivery, their therapeutic efficacy is restricted by the selective labeling of nanoparticles for uptake by reticuloendothelial system and mononuclear phagocyte system via various molecular forces, such as electrostatic, hydrophobic, and van der Waals bonds. This review article presents novel insights into surface‐modification techniques utilizing macromolecule‐mediated approaches, including PEGylation, di‐block copolymerization, and multi‐block polymerization. These techniques induce stealth properties by generating steric forces to repel micromolecular‐opsonins, such as fibrinogen, thereby mitigating opsonization effects. Moreover, advanced biological methods, like cellular hitchhiking and dysopsonic protein adsorption, are highlighted for their potential to induce biological camouflage by adsorbing onto the nanoparticulate surface, leading to immune escape. These significant findings pave the way for the development of long‐circulating next‐generation nanoplatforms capable of delivering superior therapy to patients. Future integration of artificial intelligence‐based algorithms, integrated with nanoparticle properties such as shape, size, and surface chemistry, can aid in elucidating nanoparticulate‐surface morphology and predicting interactions with the immune system, providing valuable insights into the probable path of opsonization.