Mitochondria-Targeting MoS₂-Based Nanoagents for Enhanced NIR-II Photothermal-Chemodynamic Synergistic Oncotherapy

The synergy of chemodynamic therapy (CDT) and photothermal therapy (PTT) can improve anticancer efficacy, while the limited diffusion distance and the short lifetime of •OH still greatly restrict the therapeutic efficacy of PTT-CDT. Herein, MoS2@PDA-Fe@PEG/TPP (MPFPT) nanosheets (NSs) with mitochondria-targeting ability were reported for enhanced PTT-CDT synergistic oncotherapy. MPFPT NSs were prepared by covalent modification of poly(ethylene glycol) (PEG) and triphenylphosphonium (TPP) on polydopamine (PDA)-Fe3+coated MoS2 NSs. Co-localization experiments showed that MPFPT NSs can efficiently target mitochondria via the direction of TPP. Moreover, MPFPT NSs have good photothermal performance in the second near-infrared (NIR-II) region and can greatly accelerate the Fenton reaction from H2O2 to generate more hydroxyl radicals (•OH). In vitro experimental results showed that MPFPT NSs have improved therapeutic efficacy to cancer cells than similar MoS2-based nanoagents without mitochondria-targeting units, which can be attributed to the short distance between mitochondria and MPFPT NSs and the efficient damage of mitochondria by in situ generated •OH. In the 4T1 tumor-bearing mice model, MPFPT NSs demonstrated significantly enhanced therapeutic efficacy by PTT-CDT, suggesting the superiority of the mitochondria-targeting strategy. This study reveals that mitochondria-targeting MPFPT NSs are promising nanoagents for oncotherapy.