Inflammation is a physiological response to tissue injury or infection. It is a coordinated immune reaction intended to protect the host from potentially dangerous toxins or pathogens. Acutely, inflammation is a critical component of innate immunity; however, under some circumstances, inflammation may be detrimental and potentially lethal. Chronic inflammation underlies a litany of debilitating conditions, including many top causes of death worldwide. Over the past decade, tremendous research has been undertaken to develop new treatment strategies for chronic inflammatory related diseases. While much success has been achieved, a need still exists for more targeted and innovative therapies. The objective of the first study was to investigate the ability of nanoparticles to improve the delivery of anti-inflammatory therapies to chronic inflammation sites. Here, nanoparticles, composed of poly (lactic-co-glycolic acid) (PLGA), were surface modified with mannose as a targeting ligand to macrophages, which are abundant in the chronic inflammation site. Furthermore, the nanoparticles were modified with acid-sensitive sheddable PEGylation, which would promote uptake of the nanoparticles by macrophages at the acidic inflammation site. In this work, we encapsulated betamethasone-21-acetate, an anti-inflammatory drug, into the nanoparticles and found that these formulation modifications (i.e. mannose ligand, acid-sensitive sheddable PEGylation) successfully increased the delivery of betamethasone to sites of inflammation and improved the retention of the formulation within the chronic inflammation site. The primary objective of the second study was to reduce the acute immunogenicity of a solid lipid nanoparticle formulation designed in our laboratory to deliver anti-inflammatory TNF-α siRNA to chronic inflammatory sites in a mouse model of arthritis. In previously published work, we reported the therapeutic efficacy of a solid lipid nanoparticle containing TNF-α siRNA; however, upon further investigation, this nanoparticle formulation was found to be acutely immunogenic, inducing pro-inflammatory cytokine production shortly after administration. In the second study, betamethasone-21-acetate was incorporated into the siRNA-containing solid lipid nanoparticles and tested for its ability to reduce activation of the acute immune response by the siRNA and its carrier. In this work, we found that inclusion of betamethasone successfully reduced the immunogenicity of the siRNA nanoparticle formulation, and that betamethasone, together with TNF-α siRNA, increased the ability of the TNF-α siRNA solid lipid nanoparticle formulation to reduce TNF-α production in vitro.