Gene therapy and RNA-based therapeutics are increasingly limited by the challenge of delivering fragile, anionic nucleic acids to the correct intracellular compartment. Zein, the principal maize prolamin, has attracted interest as a biodegradable, self-assembling carrier that can protect cargo and be combined with polymeric, lipidic, targeted and biomimetic components. This review critically evaluates zein-based systems for plasmid DNA, siRNA, antisense oligonucleotides and related nucleic-acid cargos. Native zein is best regarded as a protective and sustained-release matrix rather than a stand-alone high-efficiency transfection vector. In contrast, hybrid systems can add nucleic-acid condensation, colloidal stabilization, targeting and intracellular-trafficking functions through components such as chitosan, polyethylenimine, dendritic poly(l-lysine), lipids and targeting ligands. Direct evidence of endosomal escape remains limited, with only one reviewed study providing imaging evidence consistent with improved lysosomal escape. Cargo-specific evidence is strongest for plasmid DNA, with functional proof-of-concept also reported for selected siRNA and antisense oligonucleotide systems, whereas robust mRNA translation and CRISPR genome editing have not yet been demonstrated with zein-based carriers. The translational rationale for zein lies not in superior intrinsic transfection efficiency, but in route-specific protection, sustained release, hydrophobic drug co-loading and use as a biodegradable scaffold within multifunctional hybrids. Zein-based gene delivery remains preclinical and requires stronger mechanistic, cargo-specific and route-specific validation.
