Optimization of BBB-Crossing Lipid Nanoparticles for Enhanced Brain Delivery and Modulation of NLRP3 Inflammasome Signaling

Presenter: Sai Sanjeev Reddy

Faculty Sponsor: Ashish Kulkarni

School: UMass Amherst

Research Area: Chemical and Biomolecular Engineering

Session: Poster Session 6, 4:15 PM - 5:00 PM, Auditorium, A38

ABSTRACT

Effective treatment of central nervous system (CNS) disorders remains limited by the blood–brain barrier (BBB), a protective layer of cells that tightly regulates small molecule transport into the brain. Because of this selectivity, many promising drugs and nucleic‑acid therapies fail to reach effective concentrations in the brain when delivered through the bloodstream. Recent studies highlight the need for noninvasive strategies that use the body’s own transport systems, such as receptor-mediated transcytosis, to move therapeutic cargo across the BBB without damaging it. While alternative routes like nose-to-brain delivery can bypass the barrier, their efficiency varies, creating challenges for clinical translation. Thus, the need for scalable and reliable systemic delivery methods is quite relevant. Lipid nanoparticles (LNPs), already validated for nucleic‑acid delivery, are being increasingly redesigned for brain targeting. Untargeted LNPs can also reach endothelial cells that form the BBB, emphasizing the importance of measuring delivery at the level of individual cell types. Building on these advances, the present project focuses on optimizing BBB-crossing LNP formulations while measuring their influence on the NLRP3 inflammasome, a key component of innate immunity in the brain. Formulation features, such as PEG‑lipid content, cholesterol level, helper lipids, and lipid pKa, affect circulation and cellular uptake, yet few studies pair these delivery parameters with immune outcomes. This work aims to evaluate both BBB transport and NLRP3 activity to guide the design of LNPs that achieve effective brain delivery while maintaining immune and neuronal health.

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