Cascade Catalytic Nanoparticles Selectively Alkalize Cancerous Lysosomes to Suppress Cancer Progression and Metastasis

Abstract

Lysosomes are critical in modulating the progression and metastasis for various cancers. There is currently an unmet need for lysosomal alkalizers that can selectively and safely alter the pH and inhibit the function of cancer lysosomes. Here we report an effective, selective, and safe lysosomal alkalizer that can inhibit autophagy and suppress tumors in mice. Our lysosomal alkalizer consists of an FexOy core that generates hydroxyl radicals (•OH) in the presence of excessive H+ and H2O2 inside cancer lysosomes and CeO2‐z satellites that capture and convert •OH into hydroxide ions (OH−). Alkalized lysosomes, which display impaired enzyme activity and autophagy, lead to cancer cell apoptosis. We show that our alkalizer effectively inhibited both local and systemic tumor growth and metastasis in mice. Our work demonstrates that the intrinsic properties of nanoparticles can be harnessed to build effective lysosomal alkalizers that are both selective and safe.This article is protected by copyright. All rights reserved

An Alkaline Nanocage Continuously Activates Inflammasomes by Disrupting Multiorganelle Homeostasis for Efficient Pyroptosis

“…The normal physiological activities of cells are positively correlated with homeostasis and cooperation between organelles. Conversely, cell death, such as apoptosis and pyroptosis, is usually related to the destruction of the organelle homeostasis of organelles. − However, the induction of pyroptosis by disrupting single-organelle homeostasis is greatly restricted by the cytoprotective mechanisms, which are based on the cooperation between organelles. , In comparison to normal cells, cancer cells are more sensitive to imbalances in lysosomal homeostasis. , Of note, lysosome-associated autophagy plays a vital role in regulating organelle homeostasis, which is involved in ER, centrosomes, and endosomes. − Under normal conditions, ER–endosome membrane contact sites (EECS) inhibit the recruitment and subsequent transfer of the NLRP3 inflammasome to the centrosome by the endosome. , Disturbing EECS by inducing ER stress can enhance NLRP3 inflammasome activation, increasing the potential to induce pyroptosis. ,, However, lysosome-associated autophagy can alleviate ER stress by degrading the stressed ER. − In addition, the fusion of autophagosomes with lysosomes can promote the degradation of overexpressed inflammasomes. , Consequently, these cytoprotective mechanisms reduce the potential for pyroptosis mediated by disrupting single-organelle homeostasis. Therefore, it is extremely desirable to establish a new strategy to disrupt the self-protection of cells for highly efficient pyroptosis.…”