<p>Paromomycin is an aminoglycoside antibiotic widely used for cutaneous leishmaniasis therapeutics, which is considered a neglected disease by World Health Organization. Some recent studies have revealed that the patient adhesion to the treatments of cutaneous leishmaniasis with ointments form is low because it is a long-term treatment. Therefore, hydrogels are an interesting alternative to the ointment forms. Poly(vinyl alcohol) hydrogels, known for their biocompatibility and biodegradability, offer promise for paromomycin drug delivery systems. This study investigates the feasibility of cryogelated poly(vinyl alcohol) hydrogels containing sepiolite nanoparticles for controlled paromomycin release. Cryogelation, utilizing freeze-thaw cycles, creates physical crosslinks within the poly(vinyl alcohol) matrix and sepiolite was incorporated to modify hydrogel transport properties. The obtained hydrogels were characterized by DSC, TGA, and XRD. Swelling behavior in simulated body fluid showed that nanostructured hydrogels reached up to 254%. The presence of SEP and the freezing-thawing cycles increased the diffusion coefficient of the hydrogels by 150%. Chemometrics analyses were performed from the different results to optimize the number of freezing-thawing cycles and the sepiolite content on the release of paromomycin, resulting in 5 cycles and 1% SEP as the optimum condition. These initial findings suggest the potential of PVA-sepiolite hydrogels as a platform for controlled paromomycin delivery, particularly relevant for leishmaniasis treatment.</p>