Polymeric vehicles for nucleic acid delivery

Abstract

Polymeric vehicles are versatile tools for therapeutic gene delivery. Many polymers-when assembled with nucleic acids into vehicles-can protect the cargo from degradation and clearance in vivo, and facilitate its transport into intracellular compartments. Design options in polymer synthesis yield a comprehensive range of molecules and resulting vehicle formulations. These properties can be manipulated to achieve stronger association with nucleic acid cargo and cells, improved endosomal escape, or sustained delivery depending on the application. Here, we describe current approaches for polymer use and related strategies for gene delivery in preclinical and clinical applications. Polymer vehicles delivering genetic material have already achieved significant therapeutic endpoints in vitro and in animal models. From our perspective, with preclincal assays that better mimic the in vivo environment, improved strategies for target specificity, and scalable techniques for polymer synthesis, the impact of this therapeutic approach will continue to expand.

Keywords: Biocompatible; Biodegradable; Gene delivery; Gene editing; In vivo; Nanocarriers; Nanoparticle; Polymeric vehicle; Polyplex; Sustained release.

Figure 1.. Polymeric vehicles for nucleic acid delivery: cargo and formulations.

Polymeric nucleic acid delivery vehicle formulation menu including example choices of cargo, polymers, modifications, and end vehicle design. Vehicle designs include polyplexes – short-lifetime electrostatic complexes that require an excess of polymer to nucleic acids to be formed, nanoconjugates - very short-lifetime linear polycations with limited structure and random organization, micelles - MW-dependent lifetime core-shell complex composed of dynamic amphiphilic polymers, nanocapsules - natural polymer shell complex that encapsulates cargo, dendrimer - branched polymer complex with dendritic encapsulation of nucleic acids that can have peripheral functionalized for improve delivery, and nanoparticles - solid particles with homogeneous loading of nucleic acids that require degradation to assist cargo release.

Figure 2.. Extracellular and intracellular barriers to nucleic acid delivery in vivo.

A schematic illustrating physiological barriers relevant to polymeric nucleic acid carriers at the organism level, organ/tissue level, and cell level. Systemically administered vehicles must adequately circulate in the blood, accumulate in and penetrate target tissues, be internalized by target cells, and achieve intracellular cargo release.

Figure 3.. Nucleic acid delivery in polymeric vehicles grouped by target organ.

Heat maps in this figure demonstrate the relative number of publications that have described polymer delivery vehicles for targeted gene delivery per organ or tissue type. The rodent representation is compiled from approximately 100 studies between 2015 and 2020. The non-human primate is compiled from approximately 8 studies between 2005 and 2020, and the human representation is compiled from 11 clinical trials presented in Table 1. These studies were identified using key words such as “gene delivery”, “in vivo” and “polymer” in the Web of Science database. In order to be included, investigations had to report activity-based assays demonstrating effective gene delivery.