Harnessing the Therapeutic Potential of Biomacromolecules through Intracellular Delivery of Nucleic Acids, Peptides, and Proteins

Abstract

Biomacromolecules have long been at the leading edge of academic and pharmaceutical drug development and clinical translation. With the clinical advances of new therapeutics, such as monoclonal antibodies and nucleic acids, the array of medical applications of biomacromolecules has broadened considerably. A major on-going effort is to expand therapeutic targets within intracellular locations. Owing to their large sizes, abundant charges, and hydrogen-bond donors and acceptors, advanced delivery technologies are required to deliver biomacromolecules effectively inside cells. In this review, strategies used for the intracellular delivery of three major forms of biomacromolecules: nucleic acids, proteins, and peptides, are highlighted. An emphasis is placed on synthetic delivery approaches and the major hurdles needed to be overcome for their ultimate clinical translation.

Bridging polymer chemistry and cryobiology

“…However, methods of cytoplasmic translocation that do not involve endosomes, such as membrane-permeable peptides, have also been developed [48]. In addition, the introduction of medium-sized molecular drugs such as oligopeptides into cells for the control of protein-protein interactions has recently attracted considerable interest [49].…”

Dose-Dependent Nuclear Delivery and Transcriptional Repression with a Cell-Penetrant MeCP2

“…Yet progress toward this goal has been exceptionally slow. Most delivery strategies 8 are inefficient, 9 rely on degradation-prone molecular scaffolds, 10 operate via undefined or multifarious mechanisms, 11 and evaluate activity using amplified or indirect assays. 9,12 We showed previously that the mini-protein ZF5.3 9,13−16 is taken up by the endosomal pathway and released efficiently into the cytosol and nucleus of live cells, 14 alone and when fused to certain protein cargos.…”

Are We There Yet? Intracellular Sensing with Luminescent Nanoparticles and FRET

“…EE is not the only approach to accessing the cytosol. Endosome-bypassing delivery pathways are of great interest, not just for NPs, but also for proteins and nucleic acids; however, such delivery is far less common than endocytic uptake. There are also caveats that readers should keep in mind: not all reports in this context are equally rigorous in demonstrating direct delivery to the cytosol rather than lack of colocalization of endolysosomal markers for other reasons; cytosolic activity may still arise from a very small efficiency of endosomal escape while sequestration still predominates; and the idea of CvME bypassing endosomes to traffic to “caveosome” organelles still sometimes appears in the NP literature, but it is no longer an accepted theory in cell biology. , Nevertheless, there are uptake methods that, at least in part, appear to bypass endocytosis and access the cytosol.…”