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

• Published in: Journal of nanobiotechnology 2023-01, Vol.21 (1), p.5-5, Article 5
• Main Authors: Choi, Hyukjun, Yeo, Mirae, Kang, Yujin, Kim, Hyo Jeong, Park, Seong Guk, Jang, Eunjung, Park, Sung Ho, Kim, Eunhee, Kang, Sebyung
• Format: Article
• Language: English
• Subjects: Animals; Cancer; Care and treatment; Catalase; Cell Line, Tumor; Development and progression; Enzymes; Health aspects; Hydrogen Peroxide; Lactate consumption; Lactate oxidase; Lactates; Lactic Acid; Metabolic regulation; Mice; Nanomedicine; Nanoparticles; Nanoparticles - therapeutic use; Neoplasms - drug therapy; Neoplasms - pathology; Oncology, Experimental; Oxidases; Physiological aspects; Tumor Microenvironment; Tumor suppression
• ISSN: 1477-3155; 1477-3155
• DOI: 10.1186/s12951-022-01762-6

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 H O with complete lactate consumption to induce drastic necrotic cell death regardless of culture condition. However, AaLS/LOX/CAT generated residual H O , 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 H O 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.