Biochemical diversity of venom extracts often occurs within a small number of shared protein families. Developing a sequestrant capable of broadspectrum neutralization across various protein isoforms within these protein families is a necessary step in creating broad-spectrum antivenom. Using directed synthetic evolution to optimize a nanoparticle (NP) formulation capable of sequestering and neutralizing venomous phospholipase A(2) (PLA(2)), we demonstrate that broadspectrum neutralization and sequestration of venomous biomacromolecules is possible via a single optimized NP formulation. Furthermore, this optimized NP showed selectivity for venomous PLA(2) over abundant serum proteins, was not cytotoxic, and showed substantially long dissociation rates from PLA(2). These findings suggest that it may show efficacy as an in vivo venom sequestrant and may serve as a generalized lipid-mediated toxin sequestrant.