Biomimetic high-density lipoprotein nanoparticles for the delivery of nucleic acid-based therapeutics

The field of delivering nucleic acids (NAs) via high-density lipoprotein-mimicking nanoparticles (HDL NPs) has shown promising advancements over the past two decades. HDL NPs are designed to efficiently bind NAs, safeguard them from degradation, and help navigate through various biological barriers to deliver them into the target cell's cytosol. Some HDL NPs allow direct cytosolic delivery of NAs by a selective mechanism with the involvement of HDL's natural receptor scavenger receptor class B type I (SR-B1). In contrast, others rely on endocytic uptake of the entire NA-loaded HDL NP. Owing to their highly biocompatible nature, ability to target clinically relevant receptors, and fine tunability, NA-loaded HDL NPs are applied to treat cancer, cardiovascular diseases, and brain malignancies. They are also emerging as potent vaccines against cancers and infectious diseases. This review focuses on various architectures of NA-loaded HDL NPs, their mechanisms for NA cellular uptake, and their therapeutic efficacy in vivo. It comprehensively covers the latest nanocarriers for NA delivery that contain HDL's apolipoproteins (ApoA-I, ApoE) or their mimetic peptides, which define the unique functional and targeting capabilities of HDL NPs.