BODIPY Photocage-Enabled Visualization and Optical Control of saRNA Delivery and Immunogenicity

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RNA-based vaccines because of their enhanced immune response and cell-free manufacturing have become a potent and economical alternative to conventional vaccination approaches during the ongoing SARS-CoV-2 pandemic. The intrinsic single-stranded nature of RNA, however, oftentimes results in chemical instability and thus attenuated efficiency. One way to circumvent this issue is to use advanced delivery strategies which can stabilize RNA structures as well as allow efficient in vivo delivery and release. The objective of this proposal is to develop a light-responsive and fluorescent self-reporting RNA delivery system through integrating NIR light activated BODIPY photocages (Bpc) into RNA-loaded cationic polymers. In the current design, Bpc function both as the emissive self-reporters and photosensitive units. The Bpc emission will allow for real-time monitoring of the nanocarrier distribution and the photocaging process will enable on-demand release of the loaded RNA using light. To further explore this delivery platform, I will also investigate the delivery and controlled release properties of the nitro-functionalized Bpc (BpcNO2), the light-dependent fluorescence change of which can serve as an internal indicator to quantify the amount of released RNA. The success of the proposed work will offer 1) a novel, straightforward and biocompatible strategy to construct NIR light responsive and fluorescence traceable RNA delivery systems which are capable of maintaining the structural integrity and ensuring the translational efficiency of RNAs and 2) a chemical biology tool to probe the in vivo distribution and modulate the dose of immunogenic RNAs.