Nebulized Bacterioruberin/Astaxanthin-Loaded Nanovesicles: Antitumoral Activity and Beyond

Area of Science:

• Biomaterials Science
• Archaeal Biotechnology
• Cancer Therapeutics

Background:

• Halophilic archaea membranes yield novel isoprenoid biomaterials with uncharacterized therapeutic potential.
• Neutral archaeolipids (NAs) are key components of archaeal membranes, including bacterioruberin, astaxanthin, and dihydrosqualene.
• Understanding the antitumoral properties of these archaeal lipids is crucial for developing new cancer treatments.

Purpose of the Study:

• To explore the antitumoral activity of neutral archaeolipids (NAs) extracted from Halorubrum tebenquichense.
• To formulate and characterize TA-nanoarchaeosomes (TA-nanoARC) for potential therapeutic applications.
• To investigate the mechanism of action and selectivity of TA-nanoARC against cancer cells and immune cells.

Main Methods:

• Extraction of total archaeolipids (TAs) from Halorubrum tebenquichense using a modified Blight and Dyer technique.
• Formulation of TA-nanoarchaeosomes (TA-nanoARC) with specific ratios of TAs, polar archaeolipids (PAs), and Tween 80.
• Characterization of TA-nanoARC size, polydispersity, and ζ potential using SAXS modelling.
• Cytotoxicity assays on A549 lung cancer cells and mTHP-1 macrophages.
• Analysis of cellular responses, including CD204/SRA-1 expression, cytokine production (IL-6, TNF-α), and lysosomal function.

Main Results:

• TA-nanoARC exhibited significant cytotoxicity against A549 cells with an IC50 comparable to docetaxel or cisplatin, while being harmless to macrophages.
• Nebulized TA-nanoARC reduced CD204/SRA-1 expression and induced pro-inflammatory activity in macrophages, similar to or exceeding lipopolysaccharide effects.
• Internalization of TA-nanoARC led to lysosomal dysfunction in A549 cells, suggesting this as the mechanism for selective cancer cell damage.
• The NAs within TA-nanoARC altered the nanostructure, reducing the hydrophobic core and enlarging the hydrophilic section of the archaeosomes.

Conclusions:

• Nebulized TA-nanoARC demonstrates potent and selective antitumoral activity against A549 cells, mediated by lysosomal dysfunction.
• These archaeal biomaterials modulate tumor-associated macrophage phenotype, suggesting a dual mechanism of action.
• TA-nanoARC represents a promising drug-free therapeutic strategy for cancer treatment, leveraging novel biomaterials from halophilic archaea.