PAFerroptosis Combined with Metabolic Disturbance of Mito by p52‐ZER6 for Enhanced Cancer Immunotherapy induced by Nano‐Bacilliform‐Enzyme

Abstract

AbstractThe confused gene expressions and molecular mechanisms for mitochondrial dysfunction of traditional nanoenzymes is a challenge for tumor therapy. Herein, a nano‐bacilliform‐enzyme obtains the ability to inhibit p52‐ZER6 signal pathway, regulate the genes related to mitochondrial metabolism, and possess the GOx/CAT/POD‐like property. NBE acquires catalytic activity from the electronic energy transition. The tannin of NBE as a mitochondrial (Mito)‐targeting guide overloads MitoROS, and then metabolic disorder and lipid peroxidation of Mito membrane occurs, thus leading to a novel death pathway called PAFerroptosis (pyroptosis, apoptosis, and Ferroptosis). Simultaneously, in order to refrain from mitophagy, hydroxychloroquine is mixed with NBE to form a combo with strength pyroptosis. As a result, NBE/combo improves the PAFerroptosis obviously by activation of CD8+T cells and inactivation of MDSC cells, up‐regulating expression of caspase‐3 signal pathway, intercepting DHODH pathway to arrive excellent antitumor effect (93%). Therefore, this study establishes a rational nanoenzyme for mitochondrial dysfunction without mitophagy for effective antitumor therapy.