(2ei) Advanced Nanoparticle and Cellular Drug Delivery Strategies for Neurological Diseases

Neurological diseases cost over $750 billion per year in the US alone, exerting physical, emotional, and financial burdens on patients, as well as their caregivers, family, and friends. Some of the most prevalent neurological diseases with devastating impacts are acute brain injuries, including traumatic brain injury (TBI). Despite heavy research investment, there are no clinically approved therapeutics for treating TBI, demanding further research investment and novel therapeutic strategies. TBI and other neurological diseases have overlapping disease hallmarks, namely neuroinflammation, oxidative stress, excitotoxicity, toxic aggregation, and impaired neurotransmitter signaling. Despite identification of promising therapeutics such as antioxidants or anti-inflammatory agents, therapeutic efficacy is severely limited by extracellular degradation and poor brain accumulation and penetration. Advanced drug delivery strategies that leverage nanotechnology and cell-mediated chemotactic delivery offer promise for advancing the frontier of therapeutic development for neurological diseases.

Ph.D. Research: During my Ph.D. in the Elizabeth Nance lab at the University of Washington, my work focused on the fields of neurobiology, drug delivery, and nanotechnology. I applied chemical engineering principles to understand nanoparticle behavior and interactions within the brain and used this knowledge for nanotherapeutic development for brain diseases. Seeking to improve therapeutic enzyme delivery by inhibiting enzymatic degradation, I developed catalase enzyme-loaded polymeric nanoparticles. By incorporating catalase within nanoparticles, catalase was protected from degradation, extending enzyme activity from 2h for free CAT to 24h in the presence of degradative proteases.¹ I also developed a tailorable organotypic whole hemisphere (OWH) brain slice model as representative models of in vivo acute brain injury processes including excitotoxity and neuroinflammation.^{2, 3} I furthermore contributed to a review on nanoparticle-based approaches for neurological disease treatment⁴ and first-authored a review on antioxidant nanoparticles for the treatment of acute brain injuries.⁵

Postdoctoral Research: During my postdoc in the Samir Mitragotri lab at Harvard University, my work focuses on understanding the peripheral immune system contributions to TBI and leveraging cell therapy for targeted delivery to inflamed brain regions. I developed hyaluronic acid/poly(ethylene glycol) hydrogel microparticle backpacks with immobilized antioxidant catalase that utilize monocytes and macrophages as the chemotactic delivery vehicle to the neuroinflammatory brain. Catalase immobilized within BPs exhibited activity for >21 days, extending activity retention >100-fold compared to free catalase (2h) and >10-fold compared to unmodified catalase-releasing BPs (24h). These catalase-immobilized backpacks show promise in reducing lesion size in a controlled cortical impact (CCI) mouse model of moderate TBI that I independently developed in-house. I have also developed protocols and led high-throughput preparation of anti-inflammatory porcine macrophages for attachment of anti-inflammatory drug-loaded microparticle backpacks for the treatment of moderate TBI in pigs (100 million macrophages per pig). As co-corresponding author, I have also published a review on the clinical status of Alzheimer’s and Parkinson’s disease focused on gleaning insights for future therapeutic strategies.⁶

Future Research: With my background and training in acute brain injury and nanoparticle and cell-mediated delivery strategies, as a future faculty member, I will leverage drug delivery strategies and therapeutic targets that focus on the local pathophysiology of brain injury in combination with peripheral contributions to brain injury. These research directions include nanoparticles attached to peripheral immune cells for brain entry that detach and release in response to the diseased brain microenvironment for greater brain penetration and applying systemic and splenic intervention strategies that bypass the necessity of overcoming the blood-brain barrier for acute brain injury neuroprotection. Ultimately, I aim to better understand acute brain injury and related neurological diseases and develop advanced drug delivery strategies for enhanced therapeutic efficacy.

Teaching Interests:

Having obtained my B.A. and Ph.D. in chemical engineering, I deeply admire and appreciate the strong chemical engineering communities at each institution I’ve matriculated at. Throughout my academic career, between my teaching experiences and mentoring 15 high school and undergraduate students, I have worked with a variety of students of all ages from different cultural and socioeconomic backgrounds and avidly support diverse and equitable learning. I am especially interested in teaching core curriculum courses on transport phenomena, as this subject fundamentally shapes how chemical engineers understand the world and approach problems. As a graduate student, I was a Teaching Assistant (TA) for Transport Processes I, Transport Processes III, and Process Design I. As a TA, I designed and presented for exam reviews and weekly recitation sections and led office hours. Additionally, in 2020-2021 during the pandemic while at Harvard, I volunteered as a virtual tutor for middle school math through Treehouse, a nonprofit organization serving foster youth, and during my undergraduate at UT Austin, I taught 6th graders chemistry and physics in an afterschool club at an underserved school in Austin. For research service, I am a reviewer for the journal Bioengineering & Translational Medicine and am serving as a session co-chair for Area 22B - Bionanotechnology and Chemical Engineers in Medicine at the upcoming 2022 AIChE Conference. I am excited to teach the next generation of chemical engineers with a strong emphasis in understanding transport fundamentals and building chemical engineering community at my future research institution.

References – ^†Authors contributed equally, ^*Corresponding author

1. Liao R, Pon J, Chungyoun M, Nance E^*. Enzymatic protection and biocompatibility screening of enzyme-loaded polymeric nanoparticles for neurotherapeutic application. Biomaterials. (2020).
2. Liao R, Wood T, Nance E^*. Superoxide dismutase reduces monosodium glutamate-induced injury in an organotypic whole hemisphere brain slice model of excitotoxicity. J Biol Eng. (2020). 1: 1-12.
3. Liao R^†, Joseph A^†, Zhang M, Helmbrecht H, McKenna M, Filteau J, Nance E^*. Nanoparticle-microglial interaction in the ischemic brain is modulated by injury duration and treatment. Bioeng Transl Med. (2020).
4. Curtis C, Zhang M, Liao R, Wood T, Nance E^*. Systems-level thinking for nanoparticle-mediated therapeutic delivery to neurological diseases. Wiley Interdiscip Rev Nanomed Nanobiotechnol. (2016). 2: e1422.
5. Liao R, Wood T, Nance E^*. Nanotherapeutic modulation of excitotoxicity and oxidative stress in acute brain injury. Nanobiomedicine. (2020). 7:
6. Chopade P^†, Chopade N^†, Gokarn A, Mitragotri S, Suja VC^†*,Liao R^†*. Current Clinical Status of Therapies for Neurodegenerative Disease. Bioeng Transl Med. (2022). Accepted.