(87a) Activation of NALP3 Inflammasome by Gold Nanoshell/Silica Core Nanoplasmonics

Gold nanoshells are particles consisting of a silica core coated in a thin gold shell used for the photothermal ablation of tumors and are currently in clinical trials. The benefit of using a nanoparticle system consisting of a silica core and gold shell layer is the relative biocompatibility of the two materials and lack of toxicity in clinical use. Nanoshell accumulation in tumors relies on the enhance permeability and retention(EPR) effect in which circulating nanoparticles extravasate into tumors due to the leaky nature of the vasculature within the rapidly expanding tumor mass. Circulating nanoparticles also accumulate in other areas as well, such as the liver, kidneys, spleen, and lungs.

Particulate has been shown to activate NALP3 inflammasome complex. Inflammasomes form high molecular weight complexes that lead to the activation of caspase-1 to cleave precursors of proinflammatory cytokines, such as pro-IL-1β and pro-IL-18. The generation of IL-1β, a potent proinflammatory cytokine, is believed to be the key mediator in the generation of a cascade of immune responses. It can recruit neutrophils and other inflammatory cells to the site of injury, promote the maturation of dendritic cells (DCs), and prime CD8⁺ T-cells, induce the differentiation of type 17 T-helper cells, and stimulate the production of various downstream molecules such as nitric oxide(NO) and proinflammatory cytokines such as IL-6 and IL-12. Generation of proinflammatory cytokines at sites of nanoparticle accumulation leads to recruitment of other immune cells to clear the particulate accumulation, but can also lead to persistent inflammation and possible tissue damage.

 In this study we show that gold nanoshells thought to be biocompatible induce inflammatory responses through NALP3 inflammasome.  Surface functionalization with polyethylene glycol(PEG) attenuated their activity of stimulating inflammasomes. Some mechanisms involved in the inflammasome complex formation in response to gold nanoshell/silica core nanoplasmonics are elucidated. Implications of our results for nanoshell enabled photothermal therapy will be discussed.