Cytosolic protein delivery offers opportunities to develop protein-based therapeutics specifically modulate intracellular processes, especially those linked to ‘undruggable’ targets. Since protein molecules are generally membrane-impermeable due to their macromolecular nature and hydrophilic property, carriers are needed to facilitate protein transport through cell membranes. Current delivery techniques usually require chemical modification or genetically engineering on cargo proteins to strengthen the binding affinity between proteins and the carriers. However, this approach is usually accompanied with complicated syntheses, and the bioactivity of proteins might be irreversibly changed after modification. There is an urgent need to develop materials that is capable of delivering native proteins into cytosol without the need of protein modification. Jia Lv et al from South China Advanced Institute for Soft Matter Science and Technology were invited to present a special overview of this issue on Biomaterials (2019, 218, 119358). In this review, they discussed recent advances in the rational design of polymers for cytosolic delivery of native proteins with distinct isoelectric points and sizes. The principles of developed polymers in cytosolic protein delivery were intensively discussed. Furthermore, the possibility of developed polymers in the delivery of therapeutic proteins to treat diseases in vivo were evaluated. This review provides theoretical and technical supports to the development of polymers for cytosolic protein delivery.
Proteins are a kind of biomolecules with uncertain charge property and large size. There are limited number of binding sites on protein surface that can be used to combine with the carriers. The complexes formed via weak interactions will disassemble easily in buffer solutions or in the presence of anionic biomolecules in physiological conditions. The disassembly of protein complexes in extracellular environments will lead to failed cytosolic delivery.The overarching challenge in this area is to prepare stable complexes of cargo proteins using cationic polymers. In this case, we need to strengthen the binding affinity between polymers and proteins and/or to reduce the repulsion force between cationic polymers in the complexes. Functional ligands could be covalently introduced to cationic polymers for stable complexation with cargo proteins (Figure 1). Based on this principle, several polymers including boronic acid-rich polymers (Figure 2), guanidium-rich polymers (Figure 3) and amphiphilic polymers including fluoropolymers (Figure 4) were designed for cytosolic protein delivery. The intracellular and in vivo protein delivery by these materials were discussed in this review article. The challenges in protein delivery area were discussed at the end of this review. The first author of this review is Jia Lv, a postdoctoral of South China Advanced Institute for Soft Matter Science and Technology.
Figure 1. The principles of developed polymers in cytosolic protein delivery. (a) Cationic polymers bind and condense nucleic acids via ionic interactions. (b) Cationic polymers have weak binding affinity with proteins due to limited number of binding sites on cargo proteins. (c) Strategies to strengthen the binding affinity and/or to reduce the repulsion force between polymers and proteins.
Figure 2. Boronic acid-rich polymers for cytosolic protein delivery. (a) Principles of boronic acid-rich polymer in complexation with cargo proteins. The polymer binds to cargo protein via a combination of ionic interaction, nitrogen-boronate coordination and cation-π interaction. (b) The chemical structure of PBA modified on dendrimer plays a critical role in cytosolic delivery of BSA. (c) The polymer shows robust efficient in the delivery of cargo proteins with different sizes and pIs. (Sci. Adv., 2019, 5, eaaw8922; Chem. Mater., 2019, 31, 1956-1965).
Figure 3. Guanidium-rich polymers for cytosolic protein delivery (Nano Lett., 2017, 17, 1678-1684; Biomaterials, 2019, 207, 1-9).
Figure 4. Fluoropolymers for cytosolic protein delivery (Nat. Commun., 2018, 9, 1377; Biomaterials, 2018, 182, 167-175; Small, 2019, 15, 1900936).
Full text link: https://doi.org/10.1016/j.biomaterials.2019.119358
Jia Lv, Qianqian Fan, Hui Wang, Yiyun Cheng*. Polymers for cytosolic protein delivery. Biomaterials, 2019, 218, 119358.