Engineering Protein Venoms as Self‐Assembling CXCR4‐Targeted Cytotoxic Nanoparticles

Protein venoms are effective cytotoxic molecules that when conveniently targeted to tumoral markers can be exploited as promising anticancer drugs. Here, it is explored whether the structurally unrelated melittin, gomesin, and CLIP71 could be functionally active when engineered, in form of GFP fusions, as self‐assembling multimeric nanoparticles. Incorporated in modular constructs including a C‐terminal polyhistidine tag and an N‐terminal peptidic ligand of the cytokine receptor CXCR4 (overexpressed in more than 20 human neoplasias), these venoms are well produced in recombinant bacteria as proteolytically stable regular nanoparticles ranging between 12 and 35 nm. Being highly fluorescent, these materials selectively penetrate, label, and kill CXCR4+ tumor cells in a CXCR4‐dependent fashion. The obtained data support the concept of recombinant venoms as promising drugs, through the precise formulation as tumor‐targeted nanomaterials for selective theragnostic applications in CXCR4+ cancers. Protein venoms are engineered to self‐assemble as fluorescent, stable nanoparticles targeted to the tumoral marker CXCR4. These materials, are successfully produced in bacteria in a recombinant form, selectively attach, penetrate, label and kill CXCR4+ cancer cells, offering a proof of concept of nanostructured venoms as promising anticancer tools useful in therapy and theragnosis.