Lactate oxidase/catalase-displaying nanoparticles efficiently consume lactate in the tumor microenvironment to effectively suppress tumor growth

Abstract

The aggressive proliferation of tumor cells often requires increased glucose uptake and excessive anaerobic glycolysis, leading to the massive production and secretion of lactate to form a unique tumor microenvironment (TME). Therefore, regulating appropriate lactate levels in the TME would be a promising approach to control tumor cell proliferation and immune suppression. To effectively consume lactate in the TME, lactate oxidase (LOX) and catalase (CAT) were displayed onto Aquifex aeolicus lumazine synthase protein nanoparticles (AaLS) to form either AaLS/LOX or AaLS/LOX/CAT. These complexes successfully consumed lactate produced by CT26 murine colon carcinoma cells under both normoxic and hypoxic conditions. Specifically, AaLS/LOX generated a large amount of H2O2 with complete lactate consumption to induce drastic necrotic cell death regardless of culture condition. However, AaLS/LOX/CAT generated residual H2O2, leading to necrotic cell death only under hypoxic condition similar to the TME. While the local administration of AaLS/LOX to the tumor site resulted in mice death, that of AaLS/LOX/CAT significantly suppressed tumor growth without any severe side effects. AaLS/LOX/CAT effectively consumed lactate to produce adequate amounts of H2O2 which sufficiently suppress tumor growth and adequately modulate the TME, transforming environments that are favorable to tumor suppressive neutrophils but adverse to tumor-supportive tumor-associated macrophages. Collectively, these findings showed that the modular functionalization of protein nanoparticles with multiple metabolic enzymes may offer the opportunity to develop new enzyme complex-based therapeutic tools that can modulate the TME by controlling cancer metabolism. Graphical Abstract

Recent progress in lactate oxidase-based drug delivery systems for enhanced cancer therapy

“…These NPs significantly inhibited CT26 tumour growth without serious side effects and improved the stability of the cascade enzyme reaction. 48 The SpyCatcher-SpyTag system binds irreversibly to proteins or peptides with fast bond formation, making it a simple and convenient technology for loading LOX. However, the SpyCatcher-SpyTag system can often only bind with two enzymes or proteins, making it difficult to assemble multiple protein-based drugs and limiting the further enrichment of LOX-related application scenarios.…”

“…Meanwhile, CAT can convert H 2 O 2 into O 2 , which many researchers have used for cascading glucose oxidase (GOX) or LOX enzyme reactions. 48 However, the amount of H 2 O 2 in TME is limited and only leads to partial lactate consumption and hypoxia relief. 49,50 To overcome this problem, Sun et al fabricated an acid-sensitive peroxisomal double hydroxide nano-enzyme, which successfully induced O 2 self-supply and self-boosted lactate consumption within CT26 tumour tissue.…”

Qigong Exercise Balances Oxygen Supply and Acid-Base to Modulate Hypoxia: A Perspective Platform toward Preemptive Health & Medicine

“…As a result, these lactate-targeting therapies may control the Warburg effect in the tumor microenvironment (TME) to cure cancer. [ 43 ].…”

Current Advances on Nanomaterials Interfering with Lactate Metabolism for Tumor Therapy

“…However, the therapeutic efficacy of LOX is limited by rapid clearance, easy degradation or inactivation, off-target effects, and toxicity. To improve the stability of LOX and its enrichment in tumor sites, some nanosized carriers, such as MOF, [94,97] cationic liposomes, [91,98] MSN, [99] hydrogel, [100] noble metal, [101] protein nanoparticles, [102] etc., have been developed for tumor-targeted delivery of LOX. Nevertheless, the catalytic efficiency of LOX is greatly limited by the insufficient supply of O 2 at tumor sites.…”