Cryptosporidiosis, a zoonotic disease caused by Cryptosporidium spp., presents major public health and veterinary challenges, particularly as reptile ownership increases globally. Nonspecific gastrointestinal signs and the low sensitivity of traditional fecal and microscopic examinations hinder diagnosis in reptiles. Although molecular diagnostics improve detection, interpretation may be confounded by prey-derived contamination. Reports of zoonotic species, including C. parvum, in reptiles underscore the One Health implications of improved diagnostic and therapeutic strategies. Cryptosporidium serpentis, a fatal gastric pathogen of snakes, remains a significant welfare concern due to limited treatment options. Nitazoxanide, the sole FDA-approved therapy, provides insufficient efficacy in immunocompetent hosts and none in neonatal or immunocompromised patients, emphasizing the need for novel interventions. Hypothesis: Formulation of paromomycin as mucus-penetrating particles (MPP) will enhance intestinal residence, improve mucosal penetration, and increase anti-cryptosporidial efficacy. Aim 1: Develop and optimize an MPP-paromomycin formulation using cationic polymers to improve mucus interaction and drug delivery. Efficacy against C. parvum and C. serpentis will be quantified via qPCR and fluorescence microscopy, with host cell safety assessed through resazurin assays. Aim 2: Evaluate pharmacokinetic and pharmacodynamic profiles of paromomycin versus MPP-paromomycin in naturally infected Western hognose snakes. Outcomes include fecal and plasma drug concentrations and a reduction in oocyst shedding. Expected Outcomes: An optimized MPP-paromomycin formulation with enhanced intestinal persistence, reduced toxicity, and increased antiparasitic activity. This work supports the development of next-generation oral therapies for Cryptosporidium and advances One Health–aligned strategies for zoonotic disease control.