Crossing biological barriers: recent advances in nanotechnology for cytosolic protein drug delivery systems

Compared with small-molecule drugs, proteins have the advantages of selectivity and high biological activity as macromolecular drugs. However, protein drugs have difficulty in effectively entering cells due to their short half-life, poor stability, large size, and limited ability to cross biological barriers, which limits their application in clinical therapy. The development of nanoscale carrier systems has shown remarkable promise in overcoming these limitations and enhancing the clinical application of protein drugs. A variety of nanoscale delivery systems for the intracellular delivery of protein drugs, such as liposomes, polymeric nanoparticles (NPs), inorganic NPs, and protein/peptides-based carriers, have been developed. This review summarizes recent strategies for the intracellular delivery of protein drugs, and analyzes their design principles and mechanisms of action. The continued integration of nanotechnology with protein drug delivery holds tremendous potential for advancing the treatment of complex diseases and improving clinical outcomes.