Inhalable Extracellular Vesicles Engineering for Lung Cancer Treatment - PROJECT SUMMARY Lung carcinoma is the leading cause of global cancer incidence and mortality, characterized by one of the lowest five-year survival rates. My overarching goal is to pioneer potent precision therapeutics for lung cancer treatment, focusing on the design of novel delivery platforms and the exploration of pathological mechanisms to identify molecular targets for disease prevention and treatment. A primary focus of my research is interleukin-12 (IL12), a next-generation anti-cancer agent recognized for its robust tumor suppressive properties. However, its clinical application is limited by significant off-target toxicity. The current standard of intratumoral injection is not feasible for treating lung cancer due to accessibility issues. In response, I have developed inhaled IL12 mRNA-loaded exosomes, achieving significant localized delivery and enhanced immunogenicity. Yet, challenges remain with the encapsulation efficiency of electroporation and the high costs associated with large-scale mRNA production. Aim 1 is to enhance IL12-induced lung cancer immunotherapy by engineering the exosome biogenesis process. This involves designing exosome- based RNA delivery platforms that enable high mRNA encapsulation, simplify scalability, and reduce costs. Exosomes also play a crucial role in mediating intercellular and inter-tissue communication, especially in pathological modulation. Emerging evidence suggests that the coexistence of lung cancer and cardiac diseases severely worsens the prognoses of lung cancer patients. Given the prevalent incidence of cardiac fibrosis, I hypothesize (Aim 2) that this condition may exacerbate lung cancer, a hypothesis supported by my preliminary data. An additional hypothesis explores the potential mechanism, hitherto unexplored, that may be mediated by cardiac fibroblast-derived exosomes. These exosomes could regulate lung tumor growth by transmitting complex biological messages. AIM 3 is dedicated to advancing precision therapy for lung cancer patients suffering from cardiac disorders. This will be accomplished by engineering exosomes endogenously loaded with therapeutic RNAs, a platform developed in Aim 1, through clarified mechanisms of heart-lung interplays in Aim 2. The K99/R00 phase represents a crucial period for honing my scientific expertise and transitioning to independence, where I will advance therapeutic systems and elucidate mechanisms to provide precision medicine for cancer patients with a high clinical association, such as those with increasing cardiac threats.
