Targeting tumor energy metabolism via simultaneous inhibition of mitochondrial respiration and glycolysis using biodegradable hydroxyapatite nanorods

Tumor cells obtain energy supply from the unique metabolic pathways of mitochondrial respiration and glycolysis, which can be used interchangeably to produce adenosine triphosphate (ATP) for survival. To simultaneously block the two metabolic pathways and sharply cut off ATP supply, a multifunctional “nanoenabled energy interrupter” (called as HNHA-GC) was prepared by attaching glucose oxidase (GOx), hyaluronic acid (HA), and 10-hydroxycamptothecin (CPT) on the surface of degradable hydroxyapatite (NHA) nanorods. After targeted delivery of HNHA-GC to the tumor site by HA, the tumor-selective acid degradation of HNHA-GC as well as the subsequent deliveries of Ca²⁺, drug CPT, and GOx take place. The released Ca²⁺ and CPT induce mitochondrial dysfunction by Ca²⁺ overload and chemotherapy respectively, while the GOx-triggered glucose oxidation inhibits glycolysis by starvation therapy (exogenous effect). The generated H₂O₂ and released CPT increase the intracellular reactive oxygen (ROS) level. Moreover, the generated H⁺ and enhanced ROS promote Ca²⁺ overload by accelerating the degradation of HNHA-GC and preventing intracellular Ca²⁺ efflux, respectively (endogenous effect). As a result, the HNHA-GC displays a promising therapeutic modality for simultaneously cutting off mitochondrial and glycolytic ATP production through a combination of Ca²⁺ overload, chemotherapy, and starvation therapy.