A dual zinc-complexation nanozyme performs synergistic chemodynamic-immunotherapy along with additional immunosuppressive microenvironment remodeling and immune evasion inhibition for efficient breast cancer treatment.

The clinical application of nanozyme mediated chemodynamic-immunotherapy is regretfully hindered because of inadequate immunogenic cell death, immunosuppressive microenvironment and robust immune evasion of tumor cells, which normally lead to the tumor metastasis and recurrence even after therapy. Herein, an engineered nanozyme (ZSBTH) with core-shell-corona structure was fabricated to overcome above drawbacks for effective treatment of both primary and metastatic breast cancer via zinc-nanozyme mediated nanocatalytic medicine, Zn2+ enhanced immunotherapy along with a reversion of immunosuppressive microenvironments, and brefeldin A (BFA, disruptor of Golgi apparatus)-induced immune escape inhibition. The ZSBTH consisted of BFA-loaded nanozyme with dual zinc-complexation modes (ZSB) as core, triphenylphosphine (TPP, target agent for mitochondria) grafted phospholipid as shell and hyaluronic acid (HA, target agent for tumor cells) as corona. During therapy, the nanozyme first accumulated in tumor cells via enhanced permeability and retention effect and HA-mediated tumor targeting. After intratumoral biodegradation of HA corona, the ZSBTH rapidly disintegrate into ZST nanozyme, Zn2+ and BFA. The ZST enter mitochondria and perform chemodynamic therapy to induce immunogenic cell death (ICD) for inhibiting tumor growth and metastasis. Simultaneously, the Zn2+ activated Caspase-1/GSDMD-dependent pyroptosis pathway, resulting in the enhancement of ICD processes. In addition, the Zn2+-overloading also reduced NAD+ expression to inhibit glycolysis process, causing the macrophages polarization from M2-to-M1 type to reverse tumor immunosuppressive microenvironment. Moreover, BFA further disrupted the Golgi apparatus (GA) to inhibit the PD-L1 production and PD-L1 mediated immune escape, which could be enhanced by the Ca2+ capture property of ZST via disruption of Ca2+ homeostasis in GA. Both in vitro and in vivo results indicated the high efficacy of ZSBTH nanozyme in suppressing tumor growth and metastasis, offering a promising strategy for breast cancer treatment.