Targeting acidogenic metabolism by engineering self-catalytic siRNA nanocarriers/nanocatalysts for amplified tumor apoptosis/ferroptosis

Nanocatalytic medicine holds great potential in inhibiting tumor progression based on the synergistic catalytic production of toxic reactive oxygen species (ROS) between fenton nanoagents and tumor-specific endogenous substances. However, the cellular self-antioxidant and detoxification mechanisms result in discounted cell killing effect of nanocatalytic therapeutics. In this work, we design and engineer an intelligent bimetallic-type metal-organic framework (MOF) nanosystem that facilitates efficient gene delivery and expression, consequently enabling dual regulation of intracellular acid metabolism and significant amplification of nanocatalytic tumor therapy through enhanced elicitation of apoptosis and ferroptosis. The endogenous RNA interference and exogenous acidic substances supplement concurrently elevated the intracellular acidity and amplified the nanocatalytic reactions-induced ferroptosis. Especially, the reduced intracellular pH-derived calcium influx caused mitochondrial calcium overload, rendering cancer cells highly susceptible to nanocatalysts-triggered oxidative stress apoptotic damage, resulting in significantly synergistic tumor suppression. This work demonstrates the concept of amplified ferroptosis/apoptosis induced by self-enhancing intelligent nanocatalytic tumor treatment through simultaneously co-targeting two specific cancer hallmarks.