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Engineered Bacillus subtilis spores represent a versatile therapeutic platform technology rather than a single drug. Bacillus subtilis is a bacterium generally recognized as safe (GRAS) that can form highly robust endospores. These spores can be genetically engineered to function as delivery vehicles for a variety of therapeutic payloads. [1, 2, 27] The engineering process typically involves modifying the bacterium to express a specific protein, such as a vaccine antigen or a therapeutic peptide, on the spore's surface (spore display) or to secrete it after germination. [13, 25, 29] The exceptional resilience of these spores allows them to survive harsh conditions, such as the acidic environment of the stomach, enabling oral administration for gut-targeted therapies or mucosal vaccination. [4, 9, 25] They are also being investigated for topical applications, where the engineered bacteria can produce drugs directly on the skin. [5, 31] Upon reaching the target site, the spores can either elicit an immune response directly or germinate into metabolically active vegetative cells that produce the therapeutic agent in situ. [20, 25] This platform is being explored for a wide range of applications, including oral vaccines (e.g., for COVID-19), the delivery of therapeutic proteins for metabolic diseases, cancer immunotherapy, and as probiotics. [8, 16, 28, 35]
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