Regenerative medicine has been defined as a collection of interventions that restore tissues and organs damaged by disease, injury, or time to normal function. This includes a range of treatments such as gene therapies, cell-based therapies, and biomechanical interventions. In this series, we focus specifically on gene therapies and their role in transforming healthcare by directly addressing genetic causes of diseases. Gene therapy stands at the forefront of modern medicine, offering the possibility of treating or curing diseases by delivering therapeutic genes to the right cells in the body.
Traditionally, viral vectors have been used for gene delivery due to their efficiency. However, concerns over their immunogenicity, toxicity, and packaging limitations have led to the development of nonviral methods and vectors. GalNAc conjugation, protamine complexes, and PEGylation are emerging as promising techniques for gene delivery. GalNAc conjugation, in particular, targets the liver by leveraging the liver’s asialoglycoprotein receptor, allowing for more efficient delivery of therapeutic molecules to hepatocytes.
Protamine complexes enhance gene delivery by condensing and protecting DNA, improving stability, and interaction with cellular membranes. They have shown promise in adenovirus-mediated cancer gene therapy by enhancing gene transfer efficiency to specific target tissues. However, the potential risk of toxicity limits their effectiveness in high doses. Further research is needed to optimize protamine for gene transfer, reduce toxicity, and enhance its ability to target specific cells.
PEGylation, the attachment of a polyethylene glycol polymer to therapeutic agents, enhances their stability, solubility, and circulation time in the body, reducing immune responses and improving therapeutic efficacy. However, PEGylation faces challenges such as reduced cellular uptake and endosomal escape, known as the “PEG dilemma.” Innovative approaches, including using different PEG polymers and stimuli-responsive PEGylation, are being explored to overcome these challenges and improve gene delivery efficiency.
GalNAc conjugation, protamine complexes, and PEGylation represent significant advancements in nonviral gene therapy methods. Each technique offers unique advantages in enhancing gene delivery, targeting, and stability. While these methods show promise in treating genetic diseases, ongoing research and development are necessary to address their limitations and optimize their effectiveness for a wider range of conditions. The combination of these nonviral methods holds the potential to extend the reach and efficacy of gene therapy, opening up new possibilities for treating genetic diseases.
