Towards next generation polymers for Gene-Delivery applications

Coronavirus disease 2019 (COVID-19) is the historical landmark for the expanding development of mRNA therapeutics. More specifically, nucleic acid-based therapies have emerged as promising and efficient approaches to treat diseases, including genetic disorders, cancers, neurological disorders. Indeed, nucleic acids can be used to correct a disease-related inherited gene by adding, removing, or replacing genetic material, or to make cells and tissues behave in a certain way by modifying gene expression (1). Importantly, nucleic acid-based therapeutics must act intracellularly, although most of them are rapidly cleared and degraded after systemic administration and do not really cross the plasma membrane.
As a result, the use of gene-delivery vectors to protect and enable their transport inside cells with therapeutic efficiency and with minimal adverse effects to patients, are essential. To date, gene-delivery vectors are mainly classified into two major categories, including viral and nonviral vectors. The use of viral vectors has raised considerable safety concerns, such as immune responses, inflammatory responses, toxicity problems, and insertional mutagenesis. Consequently, non-viral vectors, which offer non-immunogenicity, low cost, improved loading capacity and high chemical versatility, have gained significant attention for gene delivery in recent years.
While lipid nanoparticles (LNPs) as non-viral vectors, have shown distinct advantages, they face stability and storage issues (2), strong immune stimulation, complex manufacturing and formulation heterogeneity (3). Polymeric vehicles have emerged as a promising solution due to their versatile structure, ease of functionalization, and stability. To be successful, polymeric vehicles must perform multiple functions. They must efficiently load and protect nucleic acid cargo, evade the immune system and premature clearance mechanisms, achieve cellular uptake and endosomal escape, and disappear without toxicity. Designing vehicles to fulfill all of these criteria has been challenging, but recent approaches aim to enhance vehicle performance through the modification of polymer physicochemical properties (eg. composition, molecular weight, and polydispersity), architecture, surface properties, and the combination of traditional polymers to create versatile carriers. One common feature in most polymers designed for nucleic acid delivery is the incorporation of cationic groups, with two purposes: first, to aid with the loading of negatively charged nucleic acid cargo, and second, to facilitate the interaction with negatively charged glycoproteins on the cell membrane (4).

Despite obvious safety and toxicity concerns, polymer biodegradability represents one of the most critical features affecting the clinical applicability of final biomedical products because it substantially influences their biocompatibility and biosafety. In addition, the need of repeated administration in gene-based therapies, reinforces the importance of biodegradability for the design of gene-delivery vectors. Nevertheless, there is a lack of standardized biodegradation testing methods (5), especially for polymers characterization, which could reasonably rely on libraries of existing biodegradation studies of polymers in a near future.

Both naturally-derived and synthetic polymers can be biodegradable, making them potentially safer options for gene delivery. However, the challenge for reaching also high performance, requires adjusting structural physicochemical functions. The best compromise is to consider the diversity of existing polymers and tune physicochemical properties, such as: