No abstract

The gastrointestinal (GI) tract is one the biggest mucosal surface in the body and one of the primary targets for the delivery of therapeutics, including immunotherapies. GI diseases, including, e.g., inflammatory bowel disease and intestinal infections such as cholera, pose a significant public health burden and are on the rise. Many of these diseases involve inflammatory processes that can be targeted by immune modulatory therapeutics. However, nonspecific targeting of inflammation systemically can lead to significant side effects. This can be avoided by locally targeting therapeutics to the GI tract and its mucosal immune system. In this review, we discuss nanomaterial-based strategies targeting the GI mucosal immune system, including gut-associated lymphoid tissues, tissue resident immune cells, as well as GI lymph nodes, to modulate GI inflammation and disease outcomes, as well as take advantage of some of the primary mechanisms of GI immunity such as oral tolerance.

No abstract

The androgen receptor is a key regulator of prostate cancer and the principal target of current prostate cancer therapies collectively termed androgen deprivation therapies. Insensitivity to these drugs is a hallmark of progression to a terminal disease state termed castration-resistant prostate cancer. Therefore, novel therapeutic options that slow progression of castration-resistant prostate cancer and combine effectively with existing agents are in urgent need. We show that JG-98, an allosteric inhibitor of HSP70, re-sensitizes castration-resistant prostate cancer to androgen deprivation drugs by targeting mitochondrial HSP70 (HSPA9) to suppress aerobic respiration. Rather than impacting androgen receptor stability as previously described, JG-98’s primary effect is inhibition of mitochondrial translation, leading to disruption of electron transport chain activity. Although functionally distinct from HSPA9 inhibition, direct inhibition of the electron transport chain with a complex I or II inhibitor creates a similar physiological state capable of re-sensitizing castration-resistant prostate cancer to androgen deprivation therapies. These data identify a significant role for HspA9 in mitochondrial ribosome function and highlight an actionable metabolic vulnerability of castration-resistant prostate cancer.