A pH‐Activatable Copper‐Biomineralized Proenzyme for Synergistic Chemodynamic/Chemo‐Immunotherapy against Aggressive Cancers

Abstract

Artificial enzymes have demonstrated therapeutic benefits against diverse malignant tumors, yet their antitumor potencies are still severely compromised by non‐selective catalysis, low atomic‐utilization efficiency, and undesired off‐target toxicity. Herein, it is reported that peroxidase‐like biomineralized copper (II) carbonate hydroxide nanocrystals inside single albumin nanocages (CuCH‐NCs) act as a pH‐activatable proenzyme to achieve tumor‐selective and synergistic chemodynamic/chemo‐immunotherapy against aggressive triple‐negative breast cancers (TNBCs). These CuCH‐NCs show pH‐sensitive Cu2+ release, which spontaneously undergoes glutathione (GSH)‐mediated reduction into Cu+ species for catalyzing the evolution of H2O2 into hydroxyl radicals (·OH) in a single‐atom‐like manner to cause chemodynamic cell injury, and simultaneously activates non‐toxic disulfiram to cytotoxic complex for yielding selective chemotherapeutic damage via blocking cell proliferation and amplifying cell apoptosis. CuCH‐NCs exhibit considerable tumor‐targeting capacity with deep penetration depth, thus affording preferable efficacy against orthotopic breast tumors through synergistic chemodynamic/chemotherapy, together with good in vivo safety. Moreover, CuCH‐NCs arouse distinct immunogenic cell death effect and upregulate PD‐L1 expression upon disulfiram combination, and thus synergize with anti‐PD‐L1 antibody to activate adaptive and innate immunities, together with relieving immunosuppression, finally yielding potent antitumor efficacy against both primary and metastatic TNBCs. These results provide insights into smart and high‐performance proenzymes for synergistic therapy against aggressive cancers.

Recent advances of nanocrystals in cancer theranostics

“…96 In addition to immunotherapy targeting TNBCs (Fig. 6A), pH-activatable proenzymes have been reported by T. Li et al 97 Albumin nanocages were lled with copper(II) carbonate hydroxide NCs (CuCH-NCs). For the synthesis and application of (CuCH-NCs), biomineralization took 120 min.…”

Fe-Mediated Self-Assembled Nanodrug for Tumor Microenvironment Activated Synergistic Ferroptosis-Based-Chemodynamic/Chemo Therapy and Magnetic Resonance Imaging

“…These data showed that FL NPs-induced CDT efficiently promoted cell apoptosis. In contrast, the percentage of apoptotic cells increased to 57.68% in the DOX@FL-treated group, indicating that DOX@FL had a significantly enhanced cell-killing effect. − …”

Dual-Mechanism Tuned Engineered Polyphenols with Cascade Photocatalytic Self-Fenton Reaction for Sustainable Biocidal Coatings

“…Figure2dshows that the addition of IPA (1 mM) strongly inhibited the antibacterial rate, demonstrating that hydroxyl radicals generated by photocatalysis-self-Fenton of FQM made a stronger relative contribution. Additional ESR studies were conducted to detect the •OH generated pathway in the FQM system 31. Figure 2f showed the obvious •OH (1:2:2:1), •O 2 − (six peaks), and H 2 O 2 signals with the extension of light treatment.…”