Tumor-Associated Enzyme-Activatable Spherical Nucleic Acids

Maximizing the tissue-targeting efficiency of nanomaterials while also protecting them from rapid clearance from the bloodstream and limiting their immunogenicity remains a central problem in the field of systemic-administered nanomedicine. Herein, we introduce a generalizable strategy to simultaneously increase tumor accumulation, prolong blood circulation, and limit nonspecific immune activation of nanomaterials via peptide-based, tumor-responsive, sheddable coatings. Spherical nucleic acids (SNAs) were designed and synthesized to contain an exterior coating composed of zwitterionic polypeptides with recognition sequences for tumor-associated proteases. In the presence of matrix metalloproteinases (MMPs), the polypetide coating is rapidly cleaved, leading to increased cellular uptake of these SNAs, relative to SNAs containing nonsheddable shells. Moreover, the zwitterionic nature of the polypeptide shell shields the SNAs from immune system recognition, which extends their blood circulation time and improves tumor accumulation and in vivo cellular uptake relative to control SNAs with no protective coating. Taken together, these results indicate that this strategy is a viable method for increasing nanoparticle tumor accumulation and can have utility for the systemic delivery of oligonucleotides and nanomaterials to target cells in vivo with low immunogenicity.

Automated summary

This study presents a strategy to enhance tumor accumulation, prolong blood circulation, and limit non-specific immune activation of nanomaterials through peptide-based, tumor-responsive, sheddable coatings. Spherical nucleic acids (SNAs) with zwitterionic polypeptide shells containing recognition sequences for tumor-associated proteases were designed. The polypeptide coating can be rapidly cleaved in the presence of matrix metalloproteinases (MMPs), increasing cellular uptake of SNAs and shielding them from immune system recognition. This strategy shows potential for the targeted delivery of oligonucleotides and nanomaterials with low immunogenicity.