Cryptococcal Nanotherapy: Engineering a Novel Fungus-Based Platform for Improved Drug Delivery to the Central Nervous System

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Title: Cryptococcal Nanotherapy: Engineering a Novel Fungus-Based Platform for Improved Drug Delivery to the Central Nervous System PROJECT SUMMARY/ABSTRACT Neurodegenerative diseases affect more than 1.2 billion people worldwide and this figure is steadily increasing. The exact causes of neurodegenerative diseases are still not entirely understood and the FDA-approved options for such diseases, especially amyotrophic lateral sclerosis (ALS), have very minimal effects on disease progression. This limited efficacy can also be attributed to the physiological barriers of the central nervous system (CNS), the physicochemical properties of the drugs, and the lack of understanding of how the drugs impact ALS. Riluzole and Edaravone, two FDA-approved drugs for ALS, possess the ideal properties for penetrating the CNS. However, their mechanisms of action in ALS remain unclear, they are likely to be absorbed by off-target tissues and can be ejected from the CNS barriers after ALS onset. Resveratrol has been cited as a potential alternative to existing therapeutics for ALS after demonstrating neuroprotective properties in preclinical animal models of ALS and is currently being investigated in clinical trials. Resveratrol is a polyphenolic molecule that scavenges reactive oxygen species and reduces oxidative stress in neuronal mitochondria, two hallmarks of ALS. Like Riluzole and Edaravone, resveratrol experiences off-target tissue absorption. The drug delivery field has sought to address this challenge by encapsulating resveratrol with nanomaterials. Despite some success, the nanoscale formulations of resveratrol are still limited by physiological barriers and the body's clearance mechanisms. Therefore, there is a critical need for a drug delivery platform that can withstand the body's clearance mechanisms and bypass the physiological barriers of the central nervous system to enhance ALS treatment. This work proposes using the neurotropic fungus Cryptococcus neoformans (Cn) to facilitate more efficient delivery of resveratrol into the central nervous system to treat ALS. Cn is well-equipped to traverse the physiological barriers of the central nervous system by “professionally” executing three separate mechanisms to penetrate the tissue: (1) paracellular transport (2) transcellular transport (3) immune cell hitchhiking and subsequent vomocytosis. Vomocytosis is a process by which Cn liberates itself from the intracellular environment of phagocytes to promote its survival. Given these unique characteristics, Cn is an ideal candidate for engineering the desired drug delivery platform as it can bypass physiological barriers to penetrate the CNS and escape premature degradation by the immune system. The overall hypothesis is that by tethering nanoparticle- loaded resveratrol onto the surface of Cn we can improve resveratrol delivery to the CNS and modulate ALS disease progression more effectively. To address this hypothesis, the first aim will optimize the synthesis of fungal drug carriers (FDCs) and assess their functionality in vitro. The second aim will evaluate the biodistribution of FDCs, quantify the bioavailability of resveratrol in the CNS, and investigate the therapeutic efficacy of the FDCs in a preclinical ALS model. A more efficient drug delivery platform that more effectively traffics resveratrol to the CNS will not only enhance the ALS treatment but also enhance treatment for other neurodegenerative diseases.