Modulation of mitochondrial electron transport chain by pyroptosis nanoagonists for photoresponsive tumor destruction

Abstract

Programmed cell death (PCD) plays an important role in triggering the cell death fate against tumor in biomedical frontier. However, malignant tumor cells are often resistant to the commonly used apoptosis-inducing anticancer drugs due to the multi-drug resistance of cancer. Considering the mitochondria as the origin of the aerobic respiration and reactive oxygen species, we have designed a biocompatible and mitochondrial-targeting nanoassembly between oligomycin A (OA, an ATP synthase inhibitor) and IR820, which is capable of disassembly in response to NIR laser illumination for OA release, leading to the ATP synthesis inhibition within the electron transport chain, and the mitochondrial de-functioning. Moreover, this process could trigger the electron leak within mitochondria and induce burst releases of reactive oxygen species, thus activating the downstream signaling pathways of pyroptosis, an emerging mitochondria-associated PCD pathway. Such an assembled nanoagonist OA@IR820 could actively induce prominent oxidative stress-mediated pyroptosis for malignant tumor therapy both in vitro and in vivo, presenting a highly potential tumor therapeutics.