Obesity plays a primary causative role in insulin resistance and hyperglycemia that contributes to type 2 diabetes. Excess lipid storage in the liver renders activation of the resident macrophages and chronic secretion of inflammatory mediators, therefore causing or aggravating insulin resistance. Herein, we develop collaborative assemblies using a "one-pot" synthesis method for macrophage-specific delivery of small interfering RNAs (siRNAs) that target the inflammatory proteins. Ternary nanocomplex (NC) composed of the siRNA molecule, a synthetic thiol-bearing methacrylated hyaluronic acid (sm-HA) and protamine forms through an electrostatic-driven physical assembly, which is chemically crosslinked to acquire the collaboratively assembled nanocapsule (cNC) concurrently. The obtained cNC displays significantly higher stability than NC. Functional moieties as flexible assembly units can be easily equipped on cNC for long circulation, active targeting, or controlled siRNA release. cNC-F decorated with folic acid, a macrophage-targeting ligand promotes the siRNA accumulation in the activated macrophages in the liver of the obese mouse model. cNC-F loaded with siRNA targeting inflammatory indicators efficiently control the macrophage inflammatory response by reducing the expression of the inflammatory proteins (> 40% reduction) and ameliorating the insulin resistance symptoms of the obese mice.

Spurred by numerous achievements in nanoscience and nanotechnology, the evolution of nanoparticulate drug delivery systems (nano-DDSs) is in its rapid growth period and attracting considerable attention due to their unique advantages in biomedical applications. Natural particulates ranging from mammalian cells to bacteria possess their own distinctive delivery processes and mechanisms, which inspires more design and development of cell-based DDSs by integrating the innate functions of cells with the nanoscale characteristics of nanoparticles. In this review article, we focus on the recent advances in cell-based DDSs for site-specific delivery of therapeutics and enhanced treatment of diseases. The promise and perils of cell-based DDSs are also discussed.