SUMMARY

Effective treatment of brain tumors remains an unmet need. While RNA-based therapies offer several advantages over conventional approaches, their effective delivery to brain tumors remains a major challenge due to the vascular, interstitial, and cellular barriers of the brain. Although the incorporation of RNA into a nanoparticle (NP) can prolong circulation time and facilitate cellular uptake, its accumulation in the brain tumor microenvironment (TME) remains particularly poor due to the low NP permeability across the vasculature and limited interstitial transport. Microbubble enhanced focused ultrasound (MB-FUS) provides a physical method to promote the transport of a wide range of anticancer agents across the brain vessels and in the tumor core through the local application of mechanical stress. Although the promising preclinical data have led to Phase I/II clinical trials, the underlying transport dynamics that drive the observed improvement of anti-cancer agent delivery remain poorly understood which may lead to suboptimal operation and ultimately limit outcomes in ongoing clinical trials. This research integrates mathematical modeling with quantitative image analysis to provide mechanistic insights on the MB-FUS mediated mass and drug transport dynamics and identify the optimal microbubble (MB) properties, focused ultrasound (FUS) treatment protocol, and RNA nanocarrier design for effective RNA-based therapeutics delivery in brain tumors. Collectively, this work not only establishes design rules for effective RNA-based therapies against brain tumors with MB-FUS but also provides a platform for developing next-generation tunable delivery systems for RNA-based therapy in brain tumors.