The Multifaceted Role of Degradable Cobalt Nanoparticles: Dual-Target Starvation and Intracellular Acidification Engendering LC3-Associated Whole-Cell Autophagy

Cognizance of the nano–bio interaction further bolsters cancer nanomedicine. Accentuating it, we have unveiled the potential therapeutic role of a cobalt nanoparticle (Co NP), the definitive function of which has remained cryptic for decades. We have found that it interacts with two biological entities, i.e., oxygen and amino acids, and thus curtails their reservoir. We have also identified them as the prerequisites for Co NP degradation. The reaction instigates hypoxia-inducible factor 1-alpha (HIF1α) activation and engenders nutrient deprivation, respectively. The lactic acid thus generated as a consequence of metabolic modulation allowed us to meticulously design a novel combinatorial targeted therapy. This integrates the dual target starvation harnessed by the multifaceted and biomimetic Co NPs with the drug syrosingopine that begets intracellular acidification. The designed therapy further entailed metabolic, oxidative, and genotoxic stress which led to the discovery of whole-cell autophagy-mediated cell death. The underlying key molecular events propelled the whole cellular degradation, producing its death within the LC3-positive double-membrane vesicles. This is unlike the conventional macroautophagy that works by rendering cellular homeostasis and demands LC3 removal upon framing single-membrane autophagolysosomal vesicles.