Structure-function relationships of nonviral gene vectors: Lessons from antimicrobial polymers

In recent years, substantial advances have been achieved in the design and synthesis of nonviral gene vectors. However, lack of effective and biocompatible vectors still remains a major challenge that hinders their application in clinical settings. In the past decade, there has been a rapid expansion of cationic antimicrobial polymers, due to their potent, rapid, and broad-spectrum biocidal activity against resistant microbes, and biocompatible features. Given that antimicrobial polymers share common features with nonviral gene vectors in various aspects, such as membrane affinity, functional groups, physicochemical characteristics, and unique macromolecular architectures, these polymers may provide us with inspirations to overcome challenges in the design of novel vectors toward more safe and efficient gene delivery in clinic. Building off these observations, we provide here an overview of the structure-function relationships of polymers for both antimicrobial applications and gene delivery by elaborating some key structural parameters, including functional groups, charge density, hydrophobic/hydrophilic balance, MW, and macromolecular architectures. By borrowing a leaf from antimicrobial agents, great advancement in the development of newer nonviral gene vectors with high transfection efficiency and biocompatibility will be more promising. Statement of Significance: The development of gene delivery is still in the preclinical stage for the lack of effective and biocompatible vectors. Given that antimicrobial polymers share common features with gene vectors in various aspects, such as membrane affinity, functional groups, physicochemical characteristics, and unique macromolecular architectures, these polymers may provide us with inspirations to overcome challenges in the design of novel vectors toward more safe and efficient gene delivery in clinic. In this review, we systematically summarized the structure-function relationships of antimicrobial polymers and gene vectors, with which the design of more advanced nonviral gene vectors is anticipated to be further boosted in the future.