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

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.