Abstract
Direct delivery of proteins into cells avoids many drawbacks of gene delivery, and thus has emerging applications in biotherapy. However, it remains a challenging task owing to limited charges and relatively large size of proteins. Here, we report an efficient protein delivery system via the co-assembly of fluoroamphiphiles and proteins into nanoparticles. Fluorous substituents on the amphiphiles play essential roles in the formation of uniform nanoparticles, avoiding protein denaturation, efficient endocytosis, and maintaining low cytotoxicity. Structure-activity relationship studies reveal that longer fluorous chain length and higher fluorination degree contribute to more efficient protein delivery, but excess fluorophilicity on the polymer leads to the pre-assembly of fluoroamphiphiles into stable vesicles, and thus failed protein encapsulation and cytosolic delivery. This study highlights the advantage of fluoroamphiphiles over other existing strategies for intracellular protein delivery.
Highlights
Direct delivery of proteins into cells avoids many drawbacks of gene delivery, and has emerging applications in biotherapy
As a proof-of-concept, we synthesize a small library of fluoroamphiphiles by grafting fluoroalkyls to branched PEI for cytosolic protein delivery
We demonstrate that the discovered fluoroamphiphiles efficiently deliver unmodified proteins into cells without inducing cytotoxicity
Summary
Direct delivery of proteins into cells avoids many drawbacks of gene delivery, and has emerging applications in biotherapy. Many other delivery systems have been developed based on liposomes[14,15], peptides[16], polymers[17,18], and inorganic nanoparticles[19,20] These approaches still possess some limitations such as the need of protein modification, complicated synthesis, and limited transduction efficacy. As a proof-of-concept, we synthesize a small library of fluoroamphiphiles by grafting fluoroalkyls to branched PEI for cytosolic protein delivery Traditional amphiphiles such as alkaneand cycloalkane-grafted PEIs are included to reveal the effect of fluorination and highlight the advantages of fluoroamphiphiles over other existing amphiphilic materials. We demonstrate that the discovered fluoroamphiphiles efficiently deliver unmodified proteins into cells without inducing cytotoxicity
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