Nanoparticles (NPs) possess the exciting potential to engineer specific immune responses during different disease states. Although NPs are typically considered for their customizability to promote controlled delivery of a therapeutic drug or biologic, their intrinsic immunomodulatory activity remains poorly understood. Our lab had previously shown that cargo-less poly(lactic acid) (PLA)-based NPs can suppress LPS-induced proinflammatory cytokine release in bone marrow macrophages (BMMΦs). The work described in this dissertation sought to understand the mechanisms by which these particles elicit their protective effects in response to LPS stimulation. It was hypothesized that PLA-based NPs impart a multimodal, immune modifying protective effect upon BMMΦ and other innate immune cells that can be fine-tuned through alterations of the NP physicochemical properties. This activity can then be harnessed to abrogate states of severe inflammation, such as that seen during LPS-induced endotoxemia and sepsis. Using biochemical and immunological assays to assess cellular and molecular interactions between NPs and BMMΦs, we show that the surfactant characteristics of the PLA-based NPs drive the kinetics of BMMΦ uptake and act to disrupt pathogen-associated molecular pattern (PAMP) interactions at the BMMΦ cell surface. In combination with NP uptake, the polymer composition of the NP contributes to abrogate inflammatory cell signaling resulting in decreased cytokine secretions in response to LPS stimulation. Additional studies of the protein corona establish that these effects are partially driven by the constituents of the protein corona in a manner dependent on the physiological state of the biofluids in which NPs are delivered. These in vitro observations culminate in the modeling of severe inflammation via murine LPS-induced endotoxemia to establish the ability of PLA-based NPs to increase survival, decrease severity of the signs of systemic inflammation, and hasten recovery following onset of endotoxemia. The significance of this study is that it formally characterizes the intrinsic immunomodulatory activity of PLA- based NPs, a well-established nanomedicine platform. This illuminates fundamental insights into the multimodal effects of polymeric NP nano-bio interactions. This promises to aid in rational design of future polymeric NPs of increasing complexity for a wide variety of immune- mediated diseases and disorders.