Enhanced Protection Against Toxicity of Nemopilema nomurai Venom Using a PEG-EGCG/Tetracycline Hydrochloride Micellar Nanocomplex

Jellyfish stings are the most common type of marine life injuries. However, at present, the treatment measures against jellyfish stings are mostly empirical and supportive, with uncertain therapeutic outcomes, and there is a lack of specific antidotes based on the toxic mechanism of jellyfish venom in clinical practice. In our previous study, polyphenol epigallocatechin-3-gallate (EGCG) was found to neutralize the toxicity of jellyfish Nemopilema nomurai venom (NnV) in vivo and in vitro. Herein we further demonstrated that EGCG exerted its antagonistic effect against NnV through inhibiting the oxidative stress, pro-apoptotic proteins, and systemic inflammatory responses. Subsequently, we constructed a polyethylene glycol (PEG)-EGCG/tetracycline hydrochloride (HTC) co-loaded micellar nanocomplex in order to enhance the stability and bioavailability of EGCG in vivo, which successfully integrated the membrane-repair function of PEG, the enzyme inhibitory effect of HTC and the antioxidant properties of EGCG. Notably, this micellar nanocomplex demonstrated significant protective effects against both functional damage and pathological alterations in a non-lethal NnV-envenomed mouse model. When administered 1 h after NnV envenomation, EGCG (40 mg/kg), HTC and PEG-EGCG (containing 40 mg/kg EGCG) only partially improved abnormal blood biochemical indicators and moderately alleviated histopathologic damage, and PEG-EGCG/HTC containing merely 8 mg/kg EGCG completely mitigated the toxic reactions in envenomed mice. In the preventive regimen, the administration of EGCG, HTC or PEG-EGCG 30 min before exposure showed no significant improvement in abnormal blood biochemical indicators and histopathologic damage, while PEG-EGCG/HTC could still significantly improve the functional impairments and histopathologic damage of the heart and liver in NnV-envenomed mice. These findings suggest the clinical translational potential of PEG-EGCG/HTC against jellyfish envenomation.