Self-engineered binary nanoassembly enabling closed-loop glutathione depletion-amplified tumor ferroptosis.

Ferroptosis has emerged as a promising target for anticancer treatment, comprising iron-dependent lipid peroxidation and excessive accumulation of reactive oxygen species. Given that glutathione (GSH) overproduced in tumor cells antagonizes the cellular oxidation system, the reduction of GSH production has been extensively explored to induce ferroptosis. However, reducing GSH production alone is insufficient to trigger an intense lipid peroxidation storm. It is highly desirable to achieve systemic GSH depletion through simultaneous production and consumption intervention. Herein, we propose a bidirectional blockage strategy for closed-loop GSH depletion-amplified tumor ferroptosis. Sorafenib (Sor) and gambogic acid (GA) were elaborately fabricated as a self-engineered carrier-free nanoassembly without any nanocarrier materials. The PEGylated dual-drug nanoassembly enables favorable co-delivery and tumor-specific release of Sor and GA. Notably, a closed-loop GSH depletion is observed as a result of a Sor-induced decrease in GSH production and GA-accelerated GSH consumption in vitro and in vivo. As expected, this uniquely engineered dual-drug nanoassembly demonstrates vigorous antitumor activity in 4T1 breast tumor-bearing mice. This study presents a novel nanotherapeutic modality for ferroptosis-driven cancer treatment.

Enhanced Kinetic Impactor for Deflecting Large Potentially Hazardous Asteroids via Maneuvering Space Rocks.

Asteroid impacts pose a major threat to all life on Earth. The age of the dinosaurs was abruptly ended by a 10-km-diameter asteroid. Currently, a nuclear device is the only means of deflecting large Potentially Hazardous Asteroids (PHAs) away from an Earth-impacting trajectory. The Enhanced Kinetic Impactor (EKI) concept is proposed to deflect large PHAs via maneuvering space rocks. First, an unmanned spacecraft is launched to rendezvous with an intermediate Near-Earth Asteroid (NEA). Then, more than one hundred tons of rocks are collected from the NEA as the EKI. The NEA can also be captured as the EKI if the NEA is very small. Finally, the EKI is maneuvered to impact the PHA at a high speed, resulting in a significant deflection of the PHA. For example, to deflect Apophis, as much as 200 t of rocks could be collected from a NEA as the EKI based on existing engineering capabilities. The EKI can produce a velocity increment (∆v) of 39.81 mm/s in Apophis, thereby increasing the minimum geocentric distance during the close encounter in 2029 by 1,866.93 km. This mission can be completed in 3.96 years with a propellant cost of 2.98 t. Compared with a classic kinetic impactor, the deflection distance can be increased one order of magnitude. The EKI concept breaks through the limitation of the ground-based launch capability, which can significantly increase the mass of the impactor. We anticipate that our research will be a starting point for efficient planetary defense against large PHAs.