Smart Nanotechnology for Nucleic Acid Delivery

Nucleic acid-based drugs, such as DNA, messenger RNA (mRNA), small interfering RNA (siRNA), microRNA (miRNA), and gene-editing constructs, such as CRISPR/Cas, have transformed biological research and enabled new therapeutic approaches to treat genetic diseases, cancer, and infectious diseases. Nevertheless, the real use of these nucleic acids in the clinic is restricted by several biological barriers, such as enzymatic degradation, inefficient cellular uptake, fast clearance from the blood, and possible off-target effects. To address these challenges, intelligent nanotechnology has become an attractive and innovative strategy for developing well-defined, smart, and responsive delivery systems that are designed in a tailor-made fashion for the unique physicochemical characteristics of nucleic acids. This chapter provides a comprehensive summary of recent advanced smart nanocarrier platforms for nucleic acid delivery. The chapter discusses the design considerations of lipid, polymeric, inorganic, and hybrid nanocarriers with an emphasis on stimuli-responsive systems. These systems are designed to respond to endogenous stimulators (pH, redox conditions, and enzymatic activity) as well as exogenous triggers, such as light, magnetic fields, and ultrasound, for controlled and localized therapeutic delivery. This chapter includes a discussion of the essential steps of nanocarrier synthesis, physicochemical analysis, biological performance (cellular uptake), and endosomal escape. The chapter also discusses translational aspects, safety perspectives, and new therapeutic opportunities as well as the fusion of nanotechnology with gene-editing approaches and design optimization via artificial intelligence. Finally, future aspects and regulatory considerations to offer an important reference for the successful clinical translation of smart nanotechnology-based nucleic acid therapeutics are summarized.