Head and neck cancer is currently treated by concomitant chemotherapy and radiation, but local recurrence and metastatic disease remain a concern. In particular, there is a pressing need to improve treatment for advanced and metastatic head and neck squamous cell cancer (HNSCC), which has a median survival of 6 to 12 months, even with aggressive chemotherapy, alone or combined with radiation or targeted agents. Checkpoint blockade immunotherapies (CBI) with antibodies have been tried only to achieve a 20-30% response rate. Resistance to immunotherapy in HNSCC is partly attributable to the comprehensive nature of immunosuppression, where the blockade of one checkpoint can be counterbalanced by another negative regulatory pathway, and the transient nature of target-antibody engagement, allowing rapid recovery of suppressive signals. Given these challenges, siRNAs are considered a promising alternative to antibodies to enhance the benefits of CBI, based on modularity of siRNA, enabling multi-targeted therapy, and the potential for RNA interference to provide long-lasting effects. However, without a means for reliable tumor delivery, siRNA will remain sidelined for CBI and other targeted cancer therapies. Developing a safe nucleic acid carrier that achieves favorable biodistribution and tumor cell uptake upon intravenous injection would overcome the critical barrier to clinical translation of siRNA therapeutics in cancer. The Objective of this study is to enable systemic gene delivery to tumors using Nanosac, a novel soft, non-cationic polydopamine nanocapsule, which holds siRNA inside and adopts a corona of native albumin in circulation. We produce Nanosac by coating mesoporous silica nanoparticles (MSN) with siRNA, then with pol- ydopamine, and removing the sacrificial MSN core. Nanocore delivers siRNA and silences target genes with no toxicity in vitro, binds albumin, and readily extravasates and penetrates into tumors, and suppresses tumor growth as a systemic carrier of siRNA targeting PD-L1. Our Central Hypothesis is that while the cationic charge and/or exposure of nucleic acid typical of conventional synthetic gene carriers compromise circulation time, de- livery to tumors, and safety, Nanosac will overcome these challenges by its softness, encapsulation of siRNA and the non-cationic, albuminylated surface. To test this hypothesis, we will pursue three Specific Aims: (i) To optimize design and production of Nanosac for multigene targeting; (ii) To define toxicity, pharmacokinetics (PK), biodistribution (BD), and pharmacodynamics of Nanosac; (iii) To leverage systemic delivery of Nanosac and tumor targeting by image-guided radiation. The Core Innovation of this strategy is that we have pioneered Nanosac, a non-toxic, non-cationic, soft nanocapsule as a nucleic acid carrier, which overcomes limitations of conventional gene carriers, which rely on cationic charges for loading and intracellular delivery. Thereby, we have the potential not only to overcome the persistent challenge in systemic delivery of siRNA to solid tumors but to open the door to a wide range of other gene-targeting strategies.
The proposed research is relevant to public health because our new nanoparticle system enables systemic de- livery of nucleic acids, which have not translated to a standard-of-care due to the delivery challenge but would otherwise have great therapeutic potential for various diseases. Therefore, this research is consistent with the mission of the NIH, which pertains to developing resources that will assure the nation's capability to efficiently prevent and/or treat human diseases.