Engineered Bionanomaterials for Precision Delivery of Nucleic Acid Drugs

Engineered bionanomaterials, natural or engineered nano-scale biomaterials used in biomedical applications such as liposomes and polymer nanoparticles, have emerged as transformative platforms for targeted nucleic acid drug delivery, addressing critical challenges in precision therapeutics. These advanced biomaterials leverage their inherent biocompatibility, tunable surface chemistry, and nano-scale dimensions to overcome biological barriers while protecting nucleic acid payloads from enzymatic degradation. Recent breakthroughs in material functionalization strategies have enabled unprecedented spatial control, allowing precise targeting of specific tissues, cellular compartments, and even subcellular organelles. This review adopts a barrier-oriented and mechanism-driven framework to systematically examine the key delivery challenges associated with nucleic acid drugs and the rational design of nanocarriers to overcome them. It focuses on three critical dimensions: i) the structural categories and functional classifications of nucleic acid drugs; ii) design principles of representative engineered bionanomaterials; and iii) the physiological barriers encountered during delivery and strategies to overcome them through structural innovation and functional tuning. By integrating drug properties, delivery barriers, and material design into a unified conceptual framework, this review informs the development of next-generation delivery systems for precise and effective nucleic acid therapeutics.