Redox-metabolic cascade NIR-II prodrug for synchronizing compensatory HSPs/P-gp feedback with mitophagy flux impairment against intrinsic thermotolerance.

The intrinsic proteostasis of HSPs/P-gp remains formidable barriers in the multidrug resistance (MDR) and thermotolerance. To dismantle the compensatory HSPs and P-gp defense axis, we developed a metabolic reprogramming NIR-II nanoprodrug Lipid 2-DG@Au/DOX-ss, using gold liposome-nanorod loaded disulfide-doxorubicin prodrug DOX-ss and 2-deoxy-d-glucose (2-DG). Results revealed 2-DG dose-dependent metabolic perturbations of ATP, glucose, NAD+, LDH. Coupled with a 24.01-fold ROS enhancement, a 5.05-fold PINK1 surge, a 0.65-fold LC3-II accumulation, 0.29-fold p62 increase, S-phase arrest (up to 64%), intensive mitophagy flux impairment was initiated to terminal cell death via NF-κB/PINK1/LC3-II pathway. Proteomic analysis further elucidates the concurrent inhibition of HSP70 (A12A)/90/B1(27)-mediated protein folding with P-gp efflux pump downregulation and the disruption of mitochondrial autophagic clearance, as well as unveiling the potent in immune modulation, ferroptosis, and calcium homeostasis. This bioenergetics-derived nanoprodrug with HSPs/P-gp compensation and mitophagy impairment provides a precise approach for eradicating recalcitrant MDR malignancies.