Formulations derived from polyethyleneimine (PEI) serve as versatile and efficient vehicles for the delivery of genes, drugs, and vaccines that are low-immunogenic and viable alternatives to viral vectors. PEI ensures efficient endosomal escape, preventing the therapeutic cargo from degradation, enhancing uptake, and facilitating effective cytoplasmic release via the proton sponge effect. By combining PEI with tailor-made delivery vehicles, such as polymeric assemblies, lipid-based systems, and inorganic nanomaterials, enhanced targeting, safety, and therapeutic efficacy can be accomplished. PEI-based systems are capable of delivering a wide range of drugs; in particular, they are suited to delivering drugs with a negative charge. A further function of PEI is to activate antigen-presenting cells and stimulate cytokine production in order to enable the delivery of vaccines. In spite of the promise of PEI-based formulations, biocompatibility remains a substantial concern. The most effective ways to increase PEI biocompatibility include optimizing charge density, molecular weight, and branching, developing targeted and responsive delivery systems, and using chemical modifications. To pave the way for future clinical applications, we discuss strategies to increase PEI safety, as well as recent advances and prospects in PEI-based delivery approaches for gene, drug, and vaccine delivery.
