Recent advances and clinical prospects of non-viral brain-targeted gene delivery systems

Neurological disorders encompass a wide range of debilitating conditions, including neurodegenerative diseases, brain tumors, and genetic disorders. By targeting underlying genetic factors, gene therapy has shown great potential to treat neurological disorders. However, successful implementation of gene therapy critically depends on the capacity of the gene delivery system to address the multifactorial challenges associated with brain-targeted gene delivery, encompassing biosafety, blood-brain barrier (BBB) permeability, transduction efficiency, cell-type specificity, payload capacity, and immunogenic potential. Currently, viral vectors are most widely used for clinical gene therapy applications due to their high BBB-crossing and cell transfection efficiencies. However, the safety concerns and strict gene packaging limit of viral vectors greatly restrict their future potential. Non-viral gene vectors, including exosomes, lipids, polymers, and inorganic structures, have been extensively studied in the recent decade, expecting as preferred vectors for gene delivery due to their better safety, higher gene loading efficiency, lower costs, and easier tailorability. In this review, we first discuss the potentials and challenges of gene therapeutics for brain diseases. Then we summarize the recent progress of non-viral brain-targeted gene delivery vectors and examine the key technical issues for high gene delivery efficacy. In particular, we will explore the current clinical prospects and challenges associated with translating these vehicles into effective treatments for neurological disorders. Finally, we will take a perspective on the future opportunities of non-viral delivery systems for clinical gene therapy of neurological disorders.