A novel macrophage membrane-camouflaged ultra-small copper sulfide and photothermal-responsive nitric oxide donor nanocomposites for enhanced synergistic antitumor therapy.

Ultra-small copper sulfide (CuS) nanoparticles (NPs) possess exceptional photothermal performance, Fenton-like reaction activities, and multimodal imaging characteristics, while sodium nitroprusside serves as a clinical nitric oxide (NO) donor. A judicious combination of these two agents may facilitate the development of a novel multimodal synergistic antitumor strategy. In this context, we developed macrophage membrane-camouflaged and folic acid-conjugated nanocomposites (MF-SPC) that demonstrate dual responsiveness to near-infrared (NIR) laser and pH, aiming to enhance multimodal synergistic antitumor therapy. Within these biomimetic nanocomposites, sodium nitroprusside-doped Prussian blue NPs serve as the cores for inducing photothermal-responsive NO donation, while polydopamine layer embedded with CuS dots (sub-5 nm) act as the shells. This configuration not only enhances photothermal effects but also promotes Fenton-like reaction activity, glutathione depletion capabilities, and peroxidase activity. Furthermore, the dopamine groups on the shell surface facilitate folic acid modification, drug loading, and macrophage membrane camouflage. These functionalities collectively improve tumor-targeting abilities, promote immune evasion, and enhance tumor uptake. The doxorubicin-loaded MF-SPC (MDF-SPC) exhibited favorable dispersibility, stability, and pH-responsive sustained release properties. Both in vivo fluorescence imaging and NIR thermal imaging show that the MDF-SPC possessed active tumor-targeting capability. Thus, the MDF-SPC demonstrated high antitumor activity and biosafety when subjected to NIR laser irradiation in 4T1 tumor-bearing mice. Overall, the active tumor-targeting and retention capabilities, along with the rapid temperature elevations produced by PTT, allow the MDF-SPC to precisely and swiftly amplify chemodynamic therapy, gas therapy, and chemotherapy, providing a novel multimodal nanoplatform to promote antitumor therapy.