Biodegradable peptide-based nanoparticles for the in vivo sequestration and neutralization of toxic peptides

Artificial protein affinity reagents have attracted increasing attention as versatile tools in fundamental research, clinical diagnostics, and therapeutic applications. Synthetic polymers that mimic protein-protein interactions can strongly bind target molecules and neutralize their biological functions, making them cost-efficient alternatives to conventional protein-based affinity reagents. However, their poor biodegradability and complex fabrication processes hinder clinical translation. Here, we report a general strategy for constructing biodegradable, peptide-based nanoparticles (NPs) that bind and neutralize toxic peptides in the bloodstream of living mice. As a proof-of-concept, melittin, a representative toxic peptide derived from bee venom, is selected as the model target. Because melittin predominantly comprises hydrophobic and positively charged amino acids, short anionic (l-cysteic acid, C) and hydrophobic (L-tert-leucine, T) peptide blocks were synthesized under optimized aqueous conditions to obtain reproducible oligomer distributions dominated by specific species, which can bind to melittin, without the need for specialized equipment. These blocks were conjugated at an optimized C:T ratio to form C-T peptides, which subsequently crosslinked via disulfide bonds to generate C-T NPs. The resulting C-T NPs exhibited higher binding affinity than the corresponding C-T peptides, showed selective interactions with melittin even in serum, and demonstrated redox- and enzyme-responsive biodegradability. Most importantly, the C-T NPs substantially improved survival in mice lethally challenged with melittin by rapidly binding and neutralizing the toxin in the bloodstream. Collectively, these results demonstrate a comprehensive design framework for biodegradable peptide-based affinity nanomaterials.