Micelleplex-based nucleic acid therapeutics: from targeted stimuli-responsiveness to nanotoxicity and regulation

Abstract Cell-targeted nucleic acid (NA) therapeutics, either DNA- or RNA-based, have experienced considerable attention regarding their potential applications in gene expression modulation aiming at disease management. However, the therapeutic potential of NAs as selective, safe and multispecific biomolecules is principally hindered by their instability in biological fluids and deficient cellular uptake, urgently calling for intelligent design strategies such as NA loading in effective nanosystems. In this regard, NA delivery nanosystems which bypass biological hurdles and are capable of safeguarding the NA payload have been extensively explored so far. Micelleplexes consist of tailored and multifunctional micelle-like nanoassemblies of negatively-charged NAs complexed with cationic blocks, generally of polymeric nature, this way ensuring efficient NA protection and transportation, as well as enhanced cellular transfection and boosted intracellular trafficking. Herein, we review the biomedical applications of stable micelleplexes as robust and smart NA delivery nanosystems focusing on the fine-tuning of their properties toward stimuli-responsiveness and the nanosystem's versatility to accommodate distinct ligands for selective tissue-targeting purposes. Additionally, the nanosafety and regulatory considerations of micelleplexes will also be discussed toward the future clinical translation of micelleplexes for efficient NA delivery to cells, paving the way to next-generation micelleplex-based NA therapeutics.