A Versatile Supramolecular Assembly Platform for Tumor Microenvironment Motivated Drug Release and Ferroptosis Synergistic Therapy.

Abstract

We report a simplistic approach that employs complexation between poly(<i>N</i>-allylglycine) modified with 3-mercaptoacetic acid (PNAG-COOH) and a series of metal ions to construct a new type of supramolecular architecture with intriguing features that enable a versatile and advanced nanoplatform. In most cases, such complexation results in nanoscale vesicles with superior stability, which differs significantly from the precipitates of conventional carbon-chain polymers and polypeptides. We attribute this to the polar tertiary amide groups in the polypeptoid backbone that offer excellent water affinity and numerous noncovalent molecular interactions. Particularly, the PNAG-COOH/Fe²⁺ complex can generate reactive oxygen species via a Fenton reaction in the presence of H₂O₂, thus causing ferroptosis selectively in the tumor cell. In addition, a H₂O₂-modulated intracellular <i>in situ</i> morphology transition enables prompt release of doxorubicin, representing a synergistic target antitumor efficacy. The prepared supramolecular platforms present promising candidates for many applications, considering the ability to assemble with various metal ions.