Redox-responsive caveolae-mediated hybrid calcium phosphate nanovectors for the effective gene transfection

The efficient delivery and intracellular release of genes remain a huge challenge for gene therapy. Calcium phosphate (CaP) is a commonly used gene delivery vector, but traditional CaP nanoparticles have poor stability. They are too easy to aggregate to be taken up by cells. Herein mannitol-disulfide-alendronate (Man-SS-Aln) composed of a mannitol group, a disulfide bond, and a diphosphate group was synthesized and further crosslinked with calcium ions to form the hybrid calcium phosphate nanovector named CaP-MSSA. It was shown that CaP-MSSA had excellent stability, gene loading and protecting ability, redox-responsive release profiles and good biocompatibility. The hybrid CaP-MSSA nanovector was found to enhance the cellular uptake through caveolae-mediated endocytosis and realize the rapid and controlled release of loaded genes in cells through the redox-responsive property of disulfide bonds, so as to exert good gene transfection efficiency in vitro and in vivo even at a single administration, which is of great significance for the gene therapy in the clinic. This strategy highlights a promising approach to produce a stable, CaP-based gene delivery system with improved cellular uptake and redox-responsive gene release profiles for enhanced transgene expression.