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.