The impact of nanotechnology and its advancements have allowed us to explore new therapeutic modalities. To this end, we designed nanoparticles-inlaid porous microparticles (NIPMs) coloaded with small interfering RNA (siRNA) and glucagon-like peptide-1 (GLP-1) using the supercritical carbon dioxide (SC-CO2) technology as an inhalation delivery system for diabetes therapy. siRNA-encapsulating chitosan (CS) nanoparticles were first synthesized by an ionic gelation method, which resulted in particles with small sizes (100-150 nm), high encapsulation efficiency (∼94.8%), and sustained release performance (∼60% in 32 h). These CS nanoparticles were then loaded with GLP-1-dispersed poly-l-lactide (PLLA) porous microparticles (PMs) by SC-CO2-assisted precipitation with the compressed antisolvent (PCA) process. The hypoglycemic efficacy of NIPMs administered via pulmonary route in mice persisted longer due to sustained release of siRNA from CS nanoparticles and the synergistic effects of GLP-1 in PMs, which significantly inhibited the expression of dipeptidyl peptidase-4 mRNA (DPP-4-mRNA). This ecofriendly technology provides a convenient way to fabricate nanoparticle-microparticle composites for codelivery of a gene and a therapeutic peptide, which will potentially find widespread applications in the field of pharmaceutics.
Keywords: diabetes mellitus; glucagon-like peptide-1 (GLP-1); pulmonary delivery; small interfering RNA (siRNA); supercritical carbon dioxide technology.