Design and development of a robust photo-responsive block copolymer framework for tunable nucleic acid delivery and efficient gene silencing

Abstract

Nucleic acid delivery offers tremendous potential for the treatment of acquired and hereditary diseases. Despite limited successes, the use of nucleic acid therapies has been hampered by the lack of safe and efficient delivery approaches. To address this challenge, Epps, Sullivan, and coworkers developed a new nucleic acid delivery framework predicated on a photo-responsive cationic block copolymer (BCP) that enabled tunable nucleic acid binding and precise spatiotemporal control over gene expression. This innovative platform, in which the polymer moieties directly responsible for nucleic acid complexation could be cleaved from the polymer upon photo-stimulation, significantly enhancing nucleic acid release. Furthermore, temporal control over polyplex disassembly facilitated the development of a simple, and potentially universal, kinetic modeling scheme for intracellular small interfering RNA (siRNA), messenger RNA, and protein concentrations, and that model was quantitatively validated using various genes across several animal cell lines and human primary cells. This versatile BCP-based framework easily accommodated: anionic excipients that increased siRNA potency by ~200% (on a per mass basis) over comparable polyplex systems; quantum dots that unlocked theranostic applications without impacting silencing performance; and small-molecule lipid co-formulations that enhanced transfection in human primary cells. Altogether, the system described herein shows great promise for the clinical translation of gene therapeutics. A new nucleic acid delivery framework, predicated on a photo-responsive cationic block copolymer (BCP), was used to precisely tune nucleic acid binding and provide spatiotemporal control over gene expression. This innovative platform leveraged a macromolecular design in which the polymer moieties directly responsible for nucleic acid complexation were cleaved from the polymer upon photo-stimulation, significantly enhancing nucleic acid release. Temporal control over polyplex disassembly facilitated development of a potentially universal, kinetic modeling scheme for gene silencing. Furthermore, this versatile BCP-based framework easily accommodated anionic excipients and quantum dot imaging constructs.