Lactate Efflux Inhibition by Syrosingopine/LOD Co‐Loaded Nanozyme for Synergetic Self‐Replenishing Catalytic Cancer Therapy and Immune Microenvironment Remodeling

Abstract

An effective systemic mechanism regulates tumor development and progression; thus, a rational design in a one‐stone‐two‐birds strategy is meant for cancer treatment. Herein, a hollow Fe3O4 catalytic nanozyme carrier co‐loading lactate oxidase (LOD) and a clinically‐used hypotensor syrosingopine (Syr) are developed and delivered for synergetic cancer treatment by augmented self‐replenishing nanocatalytic reaction, integrated starvation therapy, and reactivating anti‐tumor immune microenvironment. The synergetic bio‐effects of this nanoplatform stemmed from the effective inhibition of lactate efflux through blocking the monocarboxylate transporters MCT1/MCT4 functions by the loaded Syr as a trigger. Sustainable production of hydrogen peroxide by catalyzation of the increasingly residual intracellular lactic acid by the co‐delivered LOD and intracellular acidification enabled the augmented self‐replenishing nanocatalytic reaction. Large amounts of produced reactive oxygen species (ROS) damaged mitochondria to inhibit oxidative phosphorylation as the substituted energy supply upon the hampered glycolysis pathway of tumor cells. Meanwhile, remodeling anti‐tumor immune microenvironment is implemented by pH gradient reversal, promoting the release of proinflammatory cytokines, restored effector T and NK cells, increased M1‐polarize tumor‐associated macrophages, and restriction of regulatory T cells. Thus, the biocompatible nanozyme platform achieved the synergy of chemodynamic/immuno/starvation therapies. This proof‐of‐concept study represents a promising candidate nanoplatform for synergetic cancer treatment.

Nanozyme-enhanced ferroptosis for cancer treatment

“…These nanozymes exhibited the ability to convert GSH to GSSG, thereby inducing ferroptosis, and effectively suppressed tumour growth in mice implanted with HepG2 cells. Other nanozymes, such as Fe 3 O 4 , can enhance antigen presentation by dendritic cells; 116 Fe 2 O 3 can modulate the polarization of tumour-associated macrophages; 117 and manganese ion-based nanozymes activate the cGAS-STING pathway to increase tumour-infiltrating CD8 + T cells. 87 Shen et al designed a nano-metal–organic framework (referred to as mFe (SS)/DG) that incorporated glucose oxidase (GOx) and adriamycin.…”

Exploring monocarboxylate transporter inhibition for cancer treatment

“…All the supposed antitumoral effects are secondary to this inhibition. Several authors also suggest the main effect of syrosingopine is due to intracellular acidification [ 148 – 150 ]. In another later publication, Benjamin [ 151 ] suggested that metformin potentiates syrosingopine through intracellular acidic stress-mediated effects.…”

Current progress in the regulation of endogenous molecules for enhanced chemodynamic therapy

“…4C ). 76 In the tumor TME, LOX could catalyze lactate to generate H 2 O 2 in situ while Syr-induced MCT4 downregulation could achieve lactate metabolism blockade, leading to continuous H 2 O 2 production and pH reduction for boosting the Fe 3 O 4 -catalyzed Fenton reaction. Owing to the augmented ROS production and the reversion of the lactate-related immunosuppressive TME, this nanoplatform caused severe immunogenic cell death in tumor cells and promoted antitumor immunity.…”