Smart nanoplatform targeting the mitochondria-P-gp axis to overcome chemoresistance for synergistic bladder cancer therapy.

Chemoresistance remains a major obstacle in bladder cancer therapy, driven by the interplay among P-glycoprotein (P-gp)-mediated drug efflux, mitochondrial metabolic reprogramming, and impaired apoptotic signaling. Here, we present a TME-responsive nanoplatform (DR@MPDA@M) composed of MPDA core shielded by manganese dioxide (MnO2) shell, enabling sequential co-delivery of doxorubicin and resveratrol for chemo-/chemodynamic/photothermal therapy. The MnO2 layer selectively degrades under the acidic and glutathione-rich TME, enabling controlled drug release while simultaneously generating Mn2+ that catalyze Fenton-like reactions to produce cytotoxic hydroxyl radicals (•OH). Notably, this design strategically targets the mitochondria-P-gp axis that resveratrol potently downregulates P-gp expression to suppress drug efflux, while the Mn2+-induced oxidative stress disrupts mitochondrial function, depleting intracellular ATP and inhibiting heat shock protein 90. The resultant energy crisis synergistically impairs P-gp-mediated efflux and sensitizes cancer cells to doxorubicin-induced apoptosis. Upon 808 nm laser irradiation, the MPDA core mediates photothermal conversion, further accelerating the Fenton-like reaction and potentiating chemotherapy. Both in vitro and in vivo bladder tumor models demonstrate that DR@MPDA@M achieves favourable tumor inhibition. This work provides a mitochondria-P-gp axis-targeted strategy that integrates chemo-/chemodynamic/photothermal therapy, offering a promising paradigm for overcoming chemoresistance in bladder cancer.