Nucleic acid-based therapeutics represent a revolutionary approach in treating genetic disorders, offering unprecedented potential for addressing pathologies at their molecular level. However, effective cellular delivery remains a critical challenge hindering their clinical implementation. While existing delivery systems, including viral vectors and lipid nanoparticles, have shown utility, they face limitations in immunogenicity, cargo capacity, and manufacturing complexity. Natural protein-based nanoparticles, derived from proteins such as albumin, ferritin, and elastin, have emerged as promising alternative delivery systems. These carriers offer distinct advantages including reduced immunogenicity, enhanced biocompatibility, and optimal biodegradation profiles. Their engineerable nature enables precise control over particle size, surface charge, and ligand conjugation, facilitating selective cellular targeting and improved pharmacokinetics. Recent technological advances have expanded the application of protein nanoparticles across various nucleic acid modalities, including mRNA, siRNA, and plasmid DNA. Extensive research has characterized these systems through rigorous in vitro and in vivo studies, advancing our understanding of their biological behavior and clinical potential. Advanced engineering methodologies have further enhanced their optimization for specific therapeutic applications. This review examines the development and potential of protein-based nanoparticles in nucleic acid delivery, highlighting their advantages and addressing current challenges. By analyzing recent advances and clinical progress, we underscore their significant potential to enhance the safety, specificity, and efficacy of nucleic acid therapeutics, potentially revolutionizing the treatment of genetic disorders.
