Peptide Coacervates as Dynamic and Interactive Depots for Tetrodotoxin in Long‐Acting Local Anesthesia
Xing Wang, Jiahao Zhang, Wen Liu, Wanqi Wang, Zeyu Zhang, Christina Tran, Qing Huang, Tianyu Yao, Zufeng Ding, Wei Zhang, Zhicheng JinABSTRACT
Hydrophilic small‐molecule therapeutics are difficult to encapsulate using conventional depot delivery systems because of their high‐water solubility and rapid diffusion. Here we report a drug‐interactive peptide coacervate platform for sustained release of tetrodotoxin (TTX), a potent site‐1 sodium channel blocker used for local anesthesia. We discovered that a mussel foot protein‐inspired peptide (Mfp3s‐pep) interacts with TTX and undergoes spontaneous self‐coacervation under physiological conditions, forming dynamic assemblies that encapsulate TTX via multivalent noncovalent interactions. The Mfp3s‐pep coacervates sequester 29% of TTX and significantly prolong its release. In a rat sciatic nerve block model, the TTX‐Mfp3s‐pep formulation extended sensory blockade up to 10.5 h and reduced systemic toxicity by 1.5‐fold, which had not been achievable with TTX alone without drug synergy. Molecular docking and molecular dynamics simulations further reveal that coacervate structures stabilize TTX through a dynamic hydrogen‐bonding network and multivalent interactions. This work establishes peptide coacervates as a potential platform for delivery of hydrophilic therapeutics.