(2it) Immunoengineering 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 poor brain accumulation and extracellular degradation. 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 PLGA-PEG nanoparticles. By incorporating catalase within nanoparticles, catalase was protected from degradation, extending enzyme activity from 2h for free catalase to 24h in the presence of degradative proteases.¹ I also developed tailorable organotypic whole hemisphere brain slice models representative of in vivo acute brain injury processes including excitotoxity, oxygen-glucose deprivation, and neuroinflammation.^{2, 3} I furthermore wrote a review on antioxidant nanoparticles for the treatment of acute brain injuries.⁴

Postdoctoral Research: My postdoctoral work in the Samir Mitragotri lab at Harvard University focuses on leveraging macrophages as a cell therapy for targeted delivery to inflammatory brain regions after TBI. I have developed microparticle backpacks that attach to the surface of macrophages without internalization, enabling macrophage hitchhiking to diseased regions for local extracellular drug action. I utilized macrophages with anti-inflammatory interleukin-4/dexamethasone loaded polymeric PLGA backpacks in high throughput for the treatment of moderate TBI in pigs (100 million macrophages per 11 treated pigs), which reduced pro-inflammatory hallmarks of microglia and lesion volume by 56% (under review⁵). For antioxidant catalase-immobilized hydrogel backpacks, I demonstrated that catalase immobilized within the hydrogel exhibited activity for >14 days, extending activity retention >100-fold compared to free catalase (2h) and >10-fold compared to catalase-releasing backpacks (24h), enhancing neuroprotection in a controlled cortical impact mouse model of moderate TBI. I have also published reviews on the clinical status of Alzheimer’s and Parkinson’s disease focused on gleaning insights for future therapeutic strategies⁶ and the current and future approaches for engineering cell surfaces.⁷

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 utilize drug delivery and immunoengineering strategies that focus on local brain interventions in combination with peripheral monocyte and neutrophil contributions to secondary brain injury. For local brain intervention, I will develop macrophage-hitchhiking nanoparticles for brain entry that detach and release in response to the diseased brain microenvironment for greater distribution throughout the brain tissue. Beyond the local brain environment, peripheral monocytes and neutrophils infiltrate the brain after TBI and exacerbate damage via amplifying oxidative stress and inflammation. To mitigate peripheral detrimental effects, I will develop therapeutic nanoparticles that target monocytes and/or neutrophils in circulation or the spleen to inhibit their entry into the brain or convert them into anti-inflammatory therapeutic effector cells. Peripheral nanoparticle strategies bypass the necessity of overcoming the blood-brain barrier for brain entry for neuroprotection. Ultimately, I aim to better understand acute brain injury and related neurological diseases from a holistic systems perspective that encompasses peripheral contributions to ultimately develop advanced drug delivery strategies for enhanced neuroprotection and eventual clinical translation.

Teaching Interests

Having obtained my B.S. and Ph.D. in chemical engineering, I deeply value the strong chemical engineering communities at each institution I’ve attended. Throughout my academic career, between my teaching experiences and mentoring 6 high school and 10 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 a semester at UT Austin, I taught 6th graders chemistry and physics in an afterschool club at an underserved school in Austin. In addition to teaching, I am invested in supporting chemical engineers and served as a session co-chair for Chemical Engineers in Medicine and Area 22B - Bionanotechnology at AIChE 2022 and will do so again at the 2023 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, ⁺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 applications. Biomaterials. (2020). 257:
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). 5.3:
4. Liao R, Wood T, Nance E^*. Nanotherapeutic modulation of excitotoxicity and oxidative stress in acute brain injury. Nanobiomedicine. (2020). 7:
5. Liao R^†, Kapate N^†, Sodemann L, Stinson T, Prakash S, Kumbhojkar N, Suja VC, Wang LW, Flanz M, Rajeev R, Villafuerte D, Shaha S, Janes M, Park KS, Dunne M, Golemb B, Hone A, Adebowale K, Clegg J, Slate A, McGuone D, Costine BA, Mitragotri S^*. Backpack-mediated anti-inflammatory macrophage therapy for the treatment of traumatic brain injury. Under review.
6. Chopade P^†, Chopade N^†, Zhao Z, Mitragotri S, Suja VC^+*, Liao R^+*. Alzheimer's and Parkinson's disease therapies in the clinic. Bioeng Transl Med. (2023). 8.1: e10367.
7. Liao R^†, Adebowale K^†, Suja VC, Kapate N, Lu A, Gao Y^+*, Mitragotri S^+*. Materials for cell surface engineering. Advanced Materials (Accepted 2023). 2210059.