Peking University found that nanomedicines efficiently manipulate tumor cell scorch death

On May 23, 2022, Nature Nanotechnology, the international top journal, published online the latest research results of Researcher Wang Yiguang, Professor Zhang Qiang’s team and researcher team of You Fuping, Institute of Systems Biology, Peking University, entitled “A pyroptosis nanotuner for cancer therapy”.

The research team has constructed a nanodrug delivery technology with different endocytotic organelles, and for the first time reported that the endocytotic maturation process of nanopharmaceuticals can control the death pattern and anti-tumor efficacy of tumor cells, and achieve safe and efficient tumor treatment strategies.

Researcher Wang Yiguang, Professor Zhang Qiang and Researcher You Fuping of Peking University are the corresponding authors of this paper, and Dr. Chen Binlong of Peking University is the first author of the paper.

Pyroptosis is a newly discovered pattern of programmed necrosis of cells that plays an important role in a variety of physiological processes such as pathogen infection, atherosclerosis, organ failure, and tumor treatment. Studies have found that many chemotherapy drugs and nanomaterials can induce uncontrollable cell scorch death, which is toxic to normal tissues and cells while killing tumor cells, resulting in serious biosecurity problems. Therefore, there is an urgent need to develop controllable and specifically induce tumor cell scorch death nanodrugs for cancer treatment. Nanodrugs are mainly injected into the cell by endocytosis, and eventually enter the lysosome after undergoing the process of endocytosis maturation. In recent years, although many nanodrugs have been able to induce different programmed cell deaths by targeting lysosomes, the effects and regulatory effects of various stages of the endocytotic maturation pathway on the cell death signaling pathway activated by nanodrugs are still unknown.

In this work, Wang Yiguang’s research team took the lead in establishing a series of nanodrugs (ANPS) with different pH transition points (pHt 5.0~7.0) based on the pH ultra-pH-sensitive (UPS) nanotechnology platform developed by the research group (JACS 2014, Nat Mater 2014, Adv Mater 2017, et al.), The intracellular early endocytosis-late endocytostosis-lysosomal pathway can be divided into up to 10 stages, with a pH difference of only 0.2 units per stage. Using ANPS nanotechnology, the team successfully delivered nanodrugs (reactive oxygen species) precisely to endocytotic organelles at specific stages and revealed the effect of endocytosis maturation on the signaling pathways and cell killing effects induced by ROS stress.

Figure 1: Schematic diagram of an ANPS nano-focus death regulator spatially manipulating tumor cell scorch death

Figure 2: The ANPS nanofoulostat controls tumor cell death patterns by a mature process in the endophyte

Using this technology, Wang Yiguang’s research team has discovered for the first time in the world that the endocytosis maturation process can manipulate the nanodrug-induced cell death signaling pathway and killing effect in space, and systematically elucidated that the reactive oxygen species targeted by the early endophatic body can efficiently induce tumor cell focus death by specifically activating the phospholipase C signaling pathway on the endophatic membrane and the downstream Caspase3/GSDME signaling pathway, while the reactive oxygen species targeted to the advanced endophytic and lysosomal stages increase through the classical lysosomal membrane permeability , causing a pattern of apoptosis with low killing efficiency.

Figure 3: AnPS nanofoulostat mediates safe and efficient antitumor effects

AnPS, a coke death nanoregulator that regulates cell death patterns and killing effects through the endocytotic maturation process, has good universality on more than a dozen tumor cells. Compared with the nanoparticles targeted by advanced endocytosis and lysosomals, the tumor inhibition effect of early endocytos-targeted nanoparticles in vitro and in vivo can be increased by 40 times and 20 times, respectively, and safe and efficient tumor treatment is achieved on a variety of subcutaneous/in situ tumor models.

This study lays the foundation for a precise targeted delivery strategy based on the rational design of cytopathy-dying nanopharmaceuticals and the endocytotic signaling pathway. The thesis work has been funded by the National Key R&D Program, the National Natural Science Foundation of China and the Beijing Municipal Natural Science Foundation. (Source: Science Network)

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