Nanozyme‐based tumor catalytic therapy has attracted widespread attention in recent years, but its therapeutic outcome is drastically diminished by species of nanozyme, concentration of substrate, pH value, and reaction temperature, etc. Herein, a novel Cu‐doped polypyrrole nanozyme (CuP) with trienzyme‐like activities, including catalase (CAT), glutathione peroxidase (GPx), and peroxidase (POD), is first proposed by a straightforward one‐step procedure, which can specifically promote O 2 and ·OH elevation but glutathione (GSH) reduction in tumor microenvironment (TME), causing irreversible oxidative stress damage to tumor cells and reversing the redox balance. The PEGylated CuP nanozyme (CuPP) has been demonstrated to efficiently reverse immunosuppressive TME by overcoming tumor hypoxia and re‐educating macrophage from pro‐tumoral M2 to anti‐tumoral M1 phenotype. More importantly, CuPP exhibits hyperthermia‐enhanced enzyme‐mimic catalytic and immunoregulatory activities, which results in intense immune responses and almost complete tumor inhibition by further combining with α PD‐L1. This work opens intriguing perspectives not only in enzyme‐catalytic nanomedicine but also in macrophage‐based tumor immunotherapy.

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Scheme 1. The schematic of synthetic procedure for CuPPy-TP and the mechanism of sono-enhanced nanocatalytic tumor therapy.

Benefiting from treating diseases at the genetic level, gene therapy has been considered a new revolution in the biomedical field. However, the extracellular and intracellular barriers during gene transport such as enzymatic degradation and endo-/lysosomal sequestration significantly compromise the therapeutic efficacy. Though photochemical internalization (PCI) has emerged as a promising approach for causing endo-/lysosomal leakage with translocation of the internalized molecules into the cytosol, its effect is still unsatisfactory due to the insufficient light penetration depth. Here, we develop tumor microenvironment-specific enhanced gene delivery by means of ROS generated from the in situ cascaded catalytic reactions in tumors involving GOx-mediated redox reaction and Mn2+-mediated Fenton-like reaction. The efficient enzymatic protection and successful endo-/lysosomal escape of cargo gene complexes have been demonstrated. Moreover, anti-Twist siRNA-loaded G@MMSNs-P exhibit tumor-specific biodegradation, excellent T1-weighted MR imaging, and significant inhibitory effects against breast cancer growth and pulmonary metastasis.

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