Abstract Details Title NanoSentinel: A Nanoparticle Carrier to Enhance Blood–Brain Barrier Delivery of Huntingtin-Lowering Therapy in Huntington’s Disease – A Conceptual Feasibility Study Topic Movement Disorders Presentation(s) P2 - Poster Session 2 (11:45 AM-12:45 PM) Poster/Presentation Number 16-009 Objective To propose and conceptually evaluate NanoSentinel, a nanoparticle-based carrier designed to transport ASOs across the BBB, improve striatal neuronal uptake, and provide real-time monitoring of delivery efficiency. Background Huntington’s disease (HD) is caused by a CAG-repeat expansion in the HTT gene leading to mutant huntingtin (mHTT) accumulation and progressive neurodegeneration. Antisense oligonucleotide (ASO) therapy (tominersen) demonstrated robust mHTT lowering in cerebrospinal fluid but failed to show clinical benefit, in part due to poor penetration into striatal medium spiny neurons. Effective blood–brain barrier (BBB) delivery remains a critical barrier to therapeutic success. Design/Methods NanoSentinel was computationally modeled as a 100–150 nm, PEG-sarcosine–coated nanoparticle with transferrin receptor (TfR)-mediated BBB transcytosis and pH-sensitive release. Simulated pharmacokinetic modeling estimated parenchymal delivery, with comparative scenarios against intrathecal free tominersen. Conceptual outcome predictions were framed across optimistic, moderate, and pessimistic efficacy ranges based on neuronal nuclear uptake efficiency and potential inflammatory activation. Results Simulations predicted ~15% BBB penetration, a substantial increase over systemic free ASOs. Predicted striatal exposure was estimated to be 3–8× higher than intrathecal tominersen in the optimistic scenario, with expected mHTT reduction of >50%. In moderate scenarios, striatal delivery achieved 1.5–3× improvement with partial therapeutic benefit. Major risks identified included endothelial trapping, poor endosomal escape, and neuroinflammation. Conclusions NanoSentinel offers a conceptual framework for overcoming the BBB barrier in huntingtin-lowering therapy. By combining targeted delivery with real-time monitoring, this platform could revive ASO-based approaches in HD by addressing limitations observed in prior clinical trials. Preclinical BBB organoid and HD mouse model studies are warranted to validate these predictions. Authors/Disclosures Piyush Roy, MBBS PRESENTER Mr. Roy has nothing to disclose.