Peptide Coacervates as Dynamic and Interactive Depots for Tetrodotoxin in Long-Acting Local Anesthesia.

Summary

This mechanistic and translational study developed a mussel foot protein-inspired peptide coacervate that binds tetrodotoxin through multivalent noncovalent interactions and enables sustained release. In rats, the formulation prolonged sensory nerve blockade to 10.5 hours and reduced systemic toxicity 1.5-fold compared with tetrodotoxin alone, while molecular simulations supported the proposed hydrogen-bonding mechanism.

Key Findings

• Mfp3s-pep spontaneously formed coacervates under physiological conditions and sequestered 29% of tetrodotoxin.
• The tetrodotoxin–Mfp3s-pep formulation prolonged sensory blockade in a rat sciatic nerve model to 10.5 hours.
• The formulation reduced systemic toxicity 1.5-fold compared with tetrodotoxin alone, with molecular modeling supporting dynamic hydrogen-bonding interactions.

Clinical Implications

The platform could eventually support longer-lasting single-injection nerve blocks and reduce systemic toxicity, but clinical use requires extensive toxicology, reproducibility, dose optimization, and human safety testing.

Limitations

• The evidence is preclinical and was generated in a rat sciatic nerve block model.
• Long-term neurotoxicity, immunogenicity, pharmacokinetics, manufacturing scalability, and human safety were not established.

Future Directions

Future studies should define dose–response relationships, tissue distribution, duration of sensory and motor block, repeat-dose safety, neurotoxicity, and efficacy in larger animal models before considering first-in-human studies.