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J."],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Botulism is a severe neuroparalytic syndrome caused by botulinum neurotoxins (BoNTs)\u2014among the most potent biological agents\u2014with an estimated human lethal dose (LD\n                    <jats:sub>50<\/jats:sub>\n                    ) of approximately 1\u00a0ng\/kg. By cleaving soluble N-ethylmaleimide\u2013sensitive factor attachment protein receptor (SNARE) proteins at cholinergic nerve terminals, BoNTs block acetylcholine release, producing potentially fatal flaccid paralysis. Despite advances in supportive care, current therapeutic options remain limited to antitoxin administration, which is effective only against circulating toxin and cannot neutralize intracellular BoNT. Consequently, patients often require prolonged mechanical ventilation and rehabilitation. To address these limitations, this review provides a comprehensive overview of botulism, spanning historical recognition, structural and mechanistic insights into BoNT activity, clinical manifestations, and current treatment strategies, while highlighting therapeutic gaps. Particular emphasis is placed on emerging preclinical interventions, including small-molecule inhibitors, antibody-based therapeutics, intracellular clearance strategies, and gene- and RNA-based modalities, reflecting rapid progress in structural biology and pharmacology. Collectively, these advances highlight both the promise and the remaining translational challenges of developing next-generation countermeasures, with implications for clinical management and biodefense preparedness.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:italic>Botulism: Pathophysiology, Clinical Presentation, and Therapeutic Landscape.<\/jats:italic>\n                    Schematic overview of botulism from exposure to treatment. BoNT exposure may occur through foodborne, infant, wound, iatrogenic, or bioterror-related routes. After systemic distribution, the toxin binds peripheral cholinergic nerve terminals, undergoes endocytosis, and translocates its light chain into the cytosol, where SNARE cleavage blocks acetylcholine release. This results in the characteristic descending paralysis of botulism, with early cranial nerve involvement followed by limb weakness and respiratory failure. The figure also highlights the limited window for antitoxin efficacy before neuronal internalization and summarizes both current therapies and emerging preclinical countermeasures aimed at neutralizing circulating toxin, enhancing intracellular clearance, or restoring neuronal function.\n                    <jats:italic>ACh, acetylcholine; BIG-IV, botulism immune globulin intravenous; BoNT, botulinum neurotoxin; HBAT, heptavalent botulism antitoxin; IV, intravenous; PROTAC, proteolysis-targeting chimera; RNA, ribonucleic acid; SNAP-25, synaptosomal-associated protein 25; SNARE, soluble N-ethylmaleimide\u2013sensitive factor attachment protein receptor; VAMP, vesicle-associated membrane protein (synaptobrevin)<\/jats:italic>\n                  <\/jats:p>","DOI":"10.1007\/s44446-026-00090-2","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T09:31:29Z","timestamp":1780392689000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Botulinum neurotoxin: from molecular pathogenesis to emerging countermeasures"],"prefix":"10.1007","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-4192-4034","authenticated-orcid":false,"given":"Sultan","family":"Almudimeegh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,2]]},"reference":[{"issue":"9","key":"90_CR1","first-page":"1059","volume":"25","author":"L Abdolmohammadi Khiav","year":"2022","unstructured":"Abdolmohammadi Khiav L, Zahmatkesh A (2022) Major pathogenic Clostridia in human and progress toward the clostridial vaccines. 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