Near-infrared activated prodrug that coordinates heat shock protein and drug resistance responses with impaired mitochondrial cleanup to overcome natural heat tolerance

A 24.01-fold increase in reactive oxygen species (ROS) was observed with the metabolic reprogramming nanoprodrug Lipid 2-DG@Au/DOX-ss.

• Dose-dependent metabolic changes in ATP, glucose, NAD⁺, and LDH were noted with 2-DG treatment.
• S-phase cell cycle arrest reached up to 64%, indicating significant disruption of cell proliferation.
• Intensive impairment of mitophagy flux was linked to terminal cell death through the NF-κB/PINK1/LC3-II pathway.
• Proteomic analysis showed concurrent inhibition of HSP70 and HSP90, along with downregulation of the P-gp efflux pump.
• The findings suggest a role for this nanoprodrug in immune modulation, ferroptosis, and calcium homeostasis.

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