The work described in this proposal investigates a novel approach to reduce drug accumulation in healthy tissues and improve the efficacy of chemotherapy. More specifically, we take advantage of recent studies demonstrating an innate immune response (epithelial tightening) that limits viral infection, and our preliminary data show that this response can be exploited to reduce the accumulation of nanoparticles in healthy tissues. The key molecule involved in signaling the tightening response is IFN-λ, and we have shown that this cytokine is produced in response to the injection of virus-like particles (lipoplexes). Moreover, pretreatment with this cytokine elicits tightening in healthy tissues without affecting delivery to the tumor. We propose that eliciting this response will permit unimpeded delivery to tumors under conditions where deposition in healthy tissues is significantly reduced. As a demonstration of these effects, tumor-bearing mice pre-treated with IFN-λ exhibited reduced accumulation of liposomal doxorubicin (Doxil®) in healthy organs, reduced toxicity, and improved survival. By characterizing the tightening response in terms of IFN-λ dose, route of administration, and timing as well as its effects on organ and skin toxicity, our experiments will identify conditions that can be used to minimize adverse effects of chemotherapy while enhancing drug accumulation in the tumor. Finally, we will explore the potential of utilizing the reduced accumulation in healthy tissues to more aggressively dose chemotherapy in two syngeneic mouse models for ovarian cancer and conduct immune profiling to assess synergistic effects of IFN-ʎ with Doxil.