Poly(allylamine)-based carriers for gene and drug delivery: Chemical functionalization, structure-function relationships, and biointerface interactions.

Abstract

Poly(allylamine) (PAH) is a cationic polymer that has attracted increasing interest for biomedical applications due to its high density of reactive primary amines and intrinsic pH responsiveness. While PAH has been primarily investigated as a non-viral gene delivery vector, its broader potential as a multifunctional platform for drug delivery and supramolecular nanostructures remains underexplored. This review provides a comprehensive and updated overview of PAH-based carriers, with particular emphasis on how chemical functionalization governs structure-function relationships and ultimately determines biological performance. Key modification strategies, including hydrophilic, hydrophobic, and bioactive conjugations, are critically discussed in terms of their impact on polyplex formation, stability, cellular uptake, cytotoxicity, and intracellular trafficking. The interplay between molecular weight, degree of substitution, and functional group chemistry is highlighted as a central design parameter for optimizing delivery efficiency. Layer-by-layer (LbL) assembly is also examined as a versatile strategy to engineer PAH-based multifunctional nanocarriers with controlled architecture and stimuli-responsive behaviour. Recent advances in pH-responsive systems, protein delivery, and hybrid nanostructures further demonstrate the adaptability of PAH-based delivery platforms across different therapeutic modalities. Despite these advances, key challenges remain in balancing efficacy and biocompatibility, as well as in achieving performance comparable to established delivery systems such as poly(ethylenimine) and lipid-based vectors. Overall, PAH represents a highly tuneable platform with significant potential for the development of next generation nanocarriers bridging gene and drug delivery applications.