Tailor-made oligonucleotide-loaded lipid-polymer nanosystems designed for bone gene therapy

Gene therapy has emerged as a tool for the treatment of systemic metabolic disorders as osteoporosis (OP). However, the design of a suitable vehicle able to efficiently load and release the genetic material on the target cells is still a challenge. Moreover, the internalization pathway of nanosystems has been described to be dependent on their surface characteristics and the cell type evaluated. In this study, we aim at obtaining PEGylated lipid-PLGA nanoparticles (NPs) with variable surface charge able to incorporate GapmeRs (single-strand antisense oligonucleotides) for OP treatment. Nanoparticles showing negative, positive, and neutral surface charge were obtained by modulating the lipid composition. All formulations showed a remarkably low polydispersity index with adequate size. NPs were loaded with GapmeRs showing a high encapsulation efficiency and a surface charge-independent oligonucleotide loading. All the formulations were adequately internalized by MSCs. Future experiments will be devoted to use the developed formulations to clarify if the intracellular distribution of hybrid NPs on mesenchymal stem cells (MSCs) is dependent on surface charge. This portfolio of NPs will serve as a tool to analyze the effect of NP surface charge on gene therapy efficiency.