A tumor microenvironment-activatable CuS@TF nanosystem with intrinsic multi-nanozyme properties for NIR-II photoacoustic imaging-guided synergistic PTT/CDT

The efficacy of single-modal chemodynamic therapy (CDT) is often restricted by the antioxidant scavenging of overexpressed glutathione (GSH) within the tumor microenvironment (TME) and insufficient catalytic kinetics. Meanwhile, traditional photothermal therapy (PTT) also faces bottlenecks of a single therapeutic mechanism and low photothermal conversion efficiency, leading to unsatisfactory overall anti-tumor outcomes. To address these challenges, we constructed a smart-responsive, core-shell multifunctional nanotheranostic platform for near-infrared-II (NIR-II) photoacoustic (PA) imaging-guided synergistic PTT/CDT. This platform utilizes copper sulfide nanoparticles (CuS) as the photothermal core, conformally coated in situ with an Fe-tannic acid (TF) metal-phenolic network (MPN) shell (CuS@TF). In the mildly acidic TME, the TF shell dissociates to expose Fe/Cu bimetallic catalytic centers possessing excellent intrinsic peroxidase-like and catalase-like activities. Driven by the synergistic reduction of endogenous GSH and tannic acid, CuS@TF not only effectively depletes antioxidant GSH but also efficiently modulates H 2 O 2 metabolism, triggering a cascade burst of highly toxic hydroxyl radicals (·OH). Furthermore, under 1064 nm laser irradiation, the highly efficient localized hyperthermia generated by the CuS core not only directly ablates the tumor but also thermodynamically boosts the catalytic kinetics of the nanozymes, achieving profound PTT-sensitized CDT. Systematic in vitro and in vivo evaluations demonstrate that, under the precise navigation of PA imaging, CuS@TF exhibits remarkable tumor eradication efficacy (with a tumor inhibition rate of ~ 96.2%) and excellent in vivo biosafety. This work provides a novel design paradigm for the development of precise synergistic tumor theranostics based on multifunctional nanozymes. Graphical