Polyplex-Based Nonviral Gene Delivery: Recent Advances in Polymer Design, Mechanisms, and Therapeutic Applications
Abstract
ABSTRACT Polyplexes are versatile, efficient nonviral vectors for gene-based therapies and offer safer alternatives to conventional viral delivery systems. Delivering nucleic acids, including DNA, RNA, and siRNA, remains challenging because of limited stability, cellular uptake, and intracellular trafficking. Formed through spontaneous electrostatic interactions between cationic polymers and negatively charged genetic material, polyplexes can help overcome these barriers. Their properties can be tailored by modifying polymer composition, molecular weight, charge ratio, and surface characteristics to improve stability, transfection efficiency, and target specificity. Compared with viral vectors, polyplexes offer low immunogenicity, biocompatibility, scalable production, and structural flexibility. This review examines the mechanisms of polyplex formation and cellular internalization, diverse polymers used in their construction, characterization methods, and recent technological advances. It also discusses their therapeutic applications in cancer, genetic disorders, and regenerative medicine. However, physiological toxicity, inadequate systemic stability, and difficulties in reproducible scale-up continue to restrict clinical translation. Clinical development also raises social and ethical concerns involving public trust and privacy. Advances in polymer chemistry and nanotechnology may enable polyplexes to cross tissue barriers, reduce off-target effects, and achieve safer, more precise gene delivery. Consequently, polyplexes represent promising next-generation carriers with strong potential for translating gene-based therapeutics into successful future clinical practice. GRAPHICAL ABSTRACT