Dynamic polyphenol nanoparticles boost cuproptosis-driven metalloimmunotherapy of breast cancer

Polyphenolic materials have been extensively explored for biomedical applications. However, most polymer-based polyphenols are synthesized by covalently grafting phenol groups on the backbone of polymers and more convenient synthetic strategy remains challenging. Herein, a general and robust strategy to synthesize polypeptide-based polyphenol via selective ortho-hydroxylation of poly(tyrosine) was developed to construct dynamic nanoparticles (GPCuD NPs) composed of Cu²⁺ and phenylboronic acid modified doxorubicin prodrug (DOX-PBA) via metal-phenol coordination interaction and pH-reversible phenylboronate ester bond, respectively. Furthermore, matrix metalloproteinase-2 (MMP-2)-cleavable GPLGLAG peptide was also included between the polyethylene glycol and polyphenol segments, endowing GPCuD NPs with tumor-specific accumulation and deep penetration through enzyme-triggered depegylation. Notably, Cu²⁺-chelated nanoparticles efficiently ameliorated the immunosuppressive tumor microenvironment via recruiting antitumor immune cells and repolarizing M2-type tumor-associated macrophages to M1 phenotype. The combination of cuproptosis-driven metalloimmunotherapy with DOX chemotherapy remarkably suppressed 4T1 orthotopic breast tumor growth by 81.9 % and established a long-term immune memory (effective memory T cells up to 30.8 %) to prevent lung metastasis. This study has demonstrated a generalizable polyphenol nanoplatform for tumor-targeted and cuproptosis-regulated combination cancer metalloimmunotherapy.