Nonviral gene carriers composed of biodegradable polymers or lipids have been considered as a safer alternative for gene carriers over viral vectors. We have developed multifunctional nanomicelles for both drug and gene delivery application. Polyethylenimine (PEI) was modified by grafting stearic acid (SA) and further formulated to polymeric micelles (PEI-SA) with positive surface charge for gene delivery evaluation. Our results showed that PEI-SA micelles provided high siRNA binding efficiency and exhibited low cytotoxicity compared with unmodified PEI. siRNA delivered by PEI-SA carriers also demonstrated significantly higher cellular uptake efficiency and stability even in the presence of serum proteins when compared with free siRNA. The post-transcriptional gene silencing efficiency was greatly improved by the polyplex formulated by 10k PEI-SA/siRNA. In the animal intratumoral model study, the combination of co-delivering doxorubicin and vascular endothelial growth factor (VEGF) siRNA delivered by PEI-SA micelles showed a promising effect on anti-tumor growth. The amphiphilic structure of PEI-SA micelles provides advantages for multifunctional tasks; such that hydrophilic shell modified with cationic charges can electrostatically interact with DNA or siRNA, and hydrophobic core can serve as a payload for hydrophobic drugs, making it truly a promising multifunctional vehicle for both genetic and chemotherapy application.

In this article, porous poly(D,L-lactide-co-glycolide) (PLGA) microsphere scaffolds with a size of ∼ 400 μm and pores of ∼ 20 μm were prepared for constructing injectable three-dimensional hepatocyte spheroids. The porous sites of PLGA microspheres provided a spatial space for hepatocyte distribution. Hepatocytes spheroids were cocultured with human umbilical vein endothelial cell, bone marrow mesenchymal stem cell, or NIH/3T3 cells by combining the porous PLGA microspheres with the relatively hydrophobic culture strategy. The combination of open porous microspheres, hepatocytes, and nonparenchymal cells was demonstrated for application in functional hepatic tissue reconstruction. Hepatocellular-specific functions can sustained up to 2 weeks in the support of coculturing with nonparenchymal cells. The spheroidal hepatocyte coculture system had the advantages of an injectable delivery, higher cell seeding density, protection from exerted shear stress, better exchange of nutrients, oxygen and metabolites, and heterotypic cell-cell contact within and between microspheres.